Pilot Study of Tetomilast in Chronic Obstructive Pulmonary Disease (COPD) Associated With Emphysema

Study Overview
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Brief Summary
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Phase 2a multicenter, randomized, double-blind, placebo-controlled study to assess the pharmacodynamics, efficacy, and safety of tetomilast in patients with emphysema.

Official Title
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A Multi-center, Randomized, Double-blind, Placebo-controlled Pilot Study to Assess the Pharmacodynamics, Efficacy and Safety of 50 mg Tetomilast Administered as Oral Tablets in Patients With Chronic Obstructive Pulmonary Disease Associated With Emphysema THIS STUDY IS CLOSED TO ENROLLMENT AND NEW SITES

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: tetomilast
* Drug: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 40-75 yrs old,inclusive. Rating of greater than or equal to 1 on the Goddard scale in assessment of emphysema severity by HRCT. FEV1: FVC greater than 70% predicted. At least 1 documented COPD exacerbation within the past year but not within 8 weeks of randomization. Current or former smokers with a cigarette smoking history of at least 20 pack-years (or equivalent) and whose smoking status has not changed 60 days prior to screening. Exclusion Criteria: Patients with asthma, active tuberculosis or bronchiectasis. A respiratory tract infection within 30 days prior to the screening visit. Any malignancy within the last 5 years with the exception of non-melanomatous skin cancer. Uncontrolled cardiovascular, endocrine, blood, or nervous system disorders. Uncontrolled condition with COPD exacerbation of level 2 or 3 in the 8-week period prior to randomization. Systemic use of corticosteroids or other immunosuppressive agents within 30 days of the screening visit. Subjects taking anticoagulants.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1 Tetomilast<br> | Drug: tetomilast<br>* Oral tetomilast 25 mg once daily for 2 weeks followed by 50 mg once daily for 2 years.<br>|
| Placebo Comparator: 2 Placebo<br> | Drug: placebo<br>* Placebo for 104 weeks (2 years)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 104 in Trough Forced Expiratory Volume in 1 Second (FEV1) | The analysis of the change from Baseline to Week 104 (last observation carried forward [LOCF]) in trough FEV1 is presented below. | Baseline to Week 104 | 
| Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels | The analysis of the change from Baseline to Week 104 (LOCF) in the 20th percentile of lung density voxels (expressed in Hounsfield unit [HU] using quantitative HCRT) by visit and lung region is presented below. | Baseline to Week 104 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Trough FEV1 From Baseline to Week 104 | The percent change for the pulmonary function tests (PFT) from baseline was calculated for each study week as follows: % change from baseline = ([value at Week X - value at baseline] /value at baseline) x 100. | Baseline to Week 104 | 
| Density Mask Score Based on Specified Thresholds Including -950 HU | The density mask score is defined as the percentage of lung density voxels that lie below a specified threshold in the lung region of interest. The higher the percentage of the participant's lung density voxels that lie below a specified threshold, the higher the level of the participant's emphysema in the lung region under consideration. Changes in the density mask score was assessed using only a single density mask threshold of -950 HU. | Baseline and Week 104 | 
| Rate of Change in the 20th Percentile of Lung Density Voxels Expressed in HU Units for the Whole Lung (Whole Right + Whole Left) From Baseline to Week 104 | The rate of change in lung density was calculated as the change in the 20th percentile of lung density voxels divided by the duration between the dates of measurement (month or year) where applicable. For example, if HRCT measurements are available over a span of 2 years, the annual rate of change was calculated as the difference over the 2 years divided by 2, where years between scans is given by years= floor(data of last scan - date of first scan + 1)/365.25. | Baseline to Week 104 | 
| Observed Rate of Change in Emphysema From Baseline to Week 104 | The level of emphysema (g/L) within in a lung region is defined as the value of the selected percentile (10th, 15th, or 20th) in HU + 1000. The rate of change in the emphysema from baseline was calculated as the change in the level of emphysema from baseline to the specified visit divided by the time in years between the baseline and specified visit (i.e., [date of visit - date of baseline visit + 1]/365.25). | Baseline to Week 104 | 
| Change From Baseline to Week 104 in Cumulative Frequency of HU | The area under the curve (AUC) is defined as the cumulative voxel frequency in HU (ie, the value of the density mask denominator). Blood samples (4 mL) for pharmacokinetic analysis were collected for the determination of plasma OPC-6535 concentrations at Predose on Day 1 and Weeks 26, 52, 78 and 104. | Baseline and Week 104 | 
| Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) | Change from baseline in CT-derived lung volumes TLC and RV are presented in the below outcome data table. | Baseline to Week 104 | 
| Change From Baseline to Week 104 in Trough RV/TLC | Change from Baseline in Trough RV/TLC is presented in the below outcome data table. | Baseline to Week 104 | 
| Change From Baseline to Week 104 in Trough Inspiratory Capacity | Change from Baseline in Trough Inspiratory Capacity is presented in the below outcome data table. | Baseline toWeek 104 | 
| Change From Baseline to Week 104 in Trough Functional Residual Capacity (FRCpleth) | Change from baseline in trough FRCpleth is presented in the below outcome data table. | Baseline to Week 104 | 
| Change From Baseline to Week 104 in Carbon Monoxide Diffusion Capacity (DLco) | Change from Baseline in DLco is presented in the below outcome data table. | Baseline to Week 104 | 
| Change From Baseline to Week 104 in Mean Specific Airway Resistance (sRaw) and Specific Conductance (sGaw) | Change from baseline in sRaw and sGaw is presented in the below outcome data table. | Baseline to Week 104 | 
| Change From Baseline to Week 104 in 7-day Average Total Symptom Score of Dyspnea, Cough and Sputum | Participants used the Breathlessness, Cough, and Sputum Scale (BCSS) as the diary to daily monitor and rate their symptoms of difficulty breathing, cough, and sputum. The scale allows patients to rate each symptom on a scale of 0 (no difficultly for breathing and sputum, or unaware of coughing) to 4 (an almost constant problem for breathing and sputum, or almost constant for cough). | Baseline to Week 104 | 
| Change From Baseline to Week 104 in 7-day Mean Number of Actuations of Rescue Medications | Participants recorded rescue medication use (albuterol and/or ipratropium bromide) in a rescue medication log. | Baseline to Week 104 | 
| Percentage of Participants With COPD Exacerbations by Group at Week 104 | For the COPD exacerbations, baseline is defined as Randomization (Day 1). COPD exacerbations, defined as an acute worsening of COPD symptoms, were classified as being in one of 3 levels: Level I (can by self-managed by the participant); Level II (requires a physician visit), or Level III (requires a hospital visit). | Baseline and Week 104 | 
| Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher) | Percentage of participants experiencing a COPD exacerbation in a level 2 or higher are presented in the below outcome data table. | Baseline and Week 104 |