Chronic Obstructive Pulmonary Disease
Conditions
Keywords
chronic obstructive pulmonary disease, COPD, emphysema
Brief summary
To investigate the efficacy and safety of OPC-6535 in COPD patients, using the measurement of trough FEV1 over time as the primary endpoint.
Interventions
DRUGtetomilast (OPC-6535)
oral administration of 12.5mg OPC-6535, once daily for 24months
DRUGplacebo
oral administration of placebo, once daily for 24months
Sponsors
Otsuka Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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
* Age 40 to 75 years, inclusive, at the time informed consent is obtained * Ability to provide own written informed consent * Agree to use an appropriate method of contraception until 3 months after the last dose of the investigational medicinal product (IMP) * A rating of 1 or higher on the Goddard scale in assessment of emphysema severity by chest CT scan at screening * Ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) of less than 70% at screening * Cigarette smoking history of at least 20 pack years at screening
Exclusion criteria
* Subjects with obstructive disorders due to bronchial asthma * Subjects receiving long-term oxygen therapy * Subjects with active tuberculosis or obvious bronchiectasis * Complication of malignant tumor * Uncontrolled cardiovascular, endocrine, blood, or nervous system disorders * Uncontrolled condition with COPD exacerbation of level 2 or 3 within 8 weeks prior to the start of washout period (within 12 weeks prior to start of treatment period)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months | Baseline, 24 months | Measurement over time (from baseline over the 24-month treatment period) and change from baseline to end of the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline at 24 Months in Total Symptom Diary Score | Baseline, 24 months | Subjects were required to keep a symptom diary throughout the entire trial period from the start of investigational medicinal product (IMP) administration in the washout period until the end of the treatment period. Assessment items included scores for shortness of breath, cough, and sputum, IMP compliance, use of salbutamol and respiratory symptom medications, and smoking status. Subjects recorded a score of between 0 and 3, with 0 indicating no symptoms and 3 indicating a high level of symptoms, for each domain. |
| Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score | Baseline, 24 months | The SGRQ is a self-administered questionnaire designed to measure and quantify the impact of chronic respiratory disease on health-related quality of life (QOL) and well-being in three domains: symptoms, activity, and impact on daily life. The SGRQ was completed by each subject prior to IMP administration at baseline and at Month 6, Month 12, Month 18, and Month 24 (end of treatment). A weighted score based on population norms for each dimension and total was evaluated. Scores were expressed as a percentage of overall impairment where 100 represented worst possible health status and 0 indicated best possible health status. Scores were calculated when less than 24% of the item scores were missing, otherwise the scores were set to missing. Where there were multiple answers for a question, the worst case was used. |
Countries
China, Japan, South Korea
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| OPC-6535 12.5 mg Oral administration of 12.5mg OPC-6535 once daily for 24 months | 192 |
| OPC-6535 25 mg Oral administration of 25mg OPC-6535 once daily for 24 months | 198 |
| OPC-6535 50 mg Oral administration of 50 mg OPC-6535 once daily for 24 months (started from 25 mg for the first 2 weeks and the dose was titrated to 50 mg from the third week) | 191 |
| Placebo Oral administration of placebo once daily for 24 months | 190 |
| Total | 771 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 12 | 7 | 12 | 11 |
| Overall Study | Death | 1 | 4 | 3 | 2 |
| Overall Study | Lost to Follow-up | 1 | 0 | 4 | 2 |
| Overall Study | Other than specified | 3 | 3 | 2 | 2 |
| Overall Study | Physician Decision | 0 | 2 | 0 | 1 |
| Overall Study | Protocol Violation | 5 | 5 | 3 | 5 |
| Overall Study | Withdrawal by Subject | 15 | 16 | 18 | 11 |
Baseline characteristics
| Characteristic | OPC-6535 12.5 mg | OPC-6535 25 mg | OPC-6535 50 mg | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 62.2 years STANDARD_DEVIATION 7.63 | 64.0 years STANDARD_DEVIATION 7.01 | 63.2 years STANDARD_DEVIATION 7.55 | 63.4 years STANDARD_DEVIATION 7.24 | 63.2 years STANDARD_DEVIATION 7.37 |
| Region of Enrollment China | 148 Participants | 148 Participants | 146 Participants | 148 Participants | 590 Participants |
| Region of Enrollment Japan | 12 Participants | 13 Participants | 10 Participants | 10 Participants | 45 Participants |
| Region of Enrollment South Korea | 32 Participants | 37 Participants | 35 Participants | 32 Participants | 136 Participants |
| Sex: Female, Male Female | 14 Participants | 7 Participants | 18 Participants | 15 Participants | 54 Participants |
| Sex: Female, Male Male | 178 Participants | 191 Participants | 173 Participants | 175 Participants | 717 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 192 | 5 / 196 | 3 / 191 | 2 / 190 |
| other Total, other adverse events | 108 / 192 | 116 / 196 | 102 / 191 | 105 / 190 |
| serious Total, serious adverse events | 47 / 192 | 47 / 196 | 50 / 191 | 46 / 190 |
Outcome results
Primary
Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months
Measurement over time (from baseline over the 24-month treatment period) and change from baseline to end of the treatment period.
Time frame: Baseline, 24 months
Population: ITT population consisted of all subjects randomized to double-blind therapy, regardless of any protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-6535 12.5 mg | Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months | -0.004 Liters | Standard Error 0.0481 |
| OPC-6535 25 mg | Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months | -0.023 Liters | Standard Error 0.0481 |
| OPC-6535 50 mg | Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months | -0.018 Liters | Standard Error 0.0473 |
| Placebo | Trough Forced Expiratory Volume in 1 Second (FEV1) Change From Baseline to 24 Months | -0.035 Liters | Standard Error 0.048 |
Secondary
Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score
The SGRQ is a self-administered questionnaire designed to measure and quantify the impact of chronic respiratory disease on health-related quality of life (QOL) and well-being in three domains: symptoms, activity, and impact on daily life. The SGRQ was completed by each subject prior to IMP administration at baseline and at Month 6, Month 12, Month 18, and Month 24 (end of treatment). A weighted score based on population norms for each dimension and total was evaluated. Scores were expressed as a percentage of overall impairment where 100 represented worst possible health status and 0 indicated best possible health status. Scores were calculated when less than 24% of the item scores were missing, otherwise the scores were set to missing. Where there were multiple answers for a question, the worst case was used.
Time frame: Baseline, 24 months
Population: ITT population consisted of all subjects randomized to double-blind therapy, regardless of any protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-6535 12.5 mg | Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score | -9.6 score on a scale | Standard Error 3.8 |
| OPC-6535 25 mg | Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score | -7.9 score on a scale | Standard Error 3.8 |
| OPC-6535 50 mg | Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score | -7.7 score on a scale | Standard Error 3.73 |
| Placebo | Change From Baseline at 24 Months in St. George's Respiratory Questionnaire (SGRQ) Total Score | -10.4 score on a scale | Standard Error 3.8 |
Secondary
Change From Baseline at 24 Months in Total Symptom Diary Score
Subjects were required to keep a symptom diary throughout the entire trial period from the start of investigational medicinal product (IMP) administration in the washout period until the end of the treatment period. Assessment items included scores for shortness of breath, cough, and sputum, IMP compliance, use of salbutamol and respiratory symptom medications, and smoking status. Subjects recorded a score of between 0 and 3, with 0 indicating no symptoms and 3 indicating a high level of symptoms, for each domain.
Time frame: Baseline, 24 months
Population: ITT population consisted of all subjects randomized to double-blind therapy, regardless of any protocol violation.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OPC-6535 12.5 mg | Change From Baseline at 24 Months in Total Symptom Diary Score | 0.063 score on a scale | Standard Error 0.0606 |
| OPC-6535 25 mg | Change From Baseline at 24 Months in Total Symptom Diary Score | 0.073 score on a scale | Standard Error 0.0606 |
| OPC-6535 50 mg | Change From Baseline at 24 Months in Total Symptom Diary Score | 0.077 score on a scale | Standard Error 0.0597 |
| Placebo | Change From Baseline at 24 Months in Total Symptom Diary Score | 0.101 score on a scale | Standard Error 0.0606 |