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

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ClinicalTrials.gov Identifier: NCT00874497
Recruitment Status : Terminated (Sponsor Terminated)
First Posted : April 2, 2009
Results First Posted : April 17, 2017
Last Update Posted : April 17, 2017
Sponsor:
Information provided by (Responsible Party):
Otsuka Pharmaceutical Development & Commercialization, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Chronic Obstructive Pulmonary Disease
Interventions Drug: tetomilast
Drug: placebo
Enrollment 84
Recruitment Details Of the 84 participants treated in the trial, 38 completed the trial and 10 participants were ongoing at the time the sponsor discontinued the trial.
Pre-assignment Details Prior to randomization, each participant was in a 28- to 35-day screening period. Placebo was given for 14 days and a daily diary of symptom scores and actuations of albuterol/ipratropium bromide were collected.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks. Participants were administered matching placebo for 104 weeks (2 years)
Period Title: Overall Study
Started 51 [1] 33 [1]
Completed 23 15
Not Completed 28 18
Reason Not Completed
Lost to Follow-up             2             4
Adverse Event             9             4
Sponsor Discontinued Trial             7             3
Met Withdrawal Criteria             4             2
Physician Decision             1             1
Withdrawal by Subject             5             4
[1]
This is the number of participants who were treated and were considered as safety population.
Arm/Group Title Tetomilast 50 mg Placebo Total
Hide Arm/Group Description Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks. Participants were administered matching placebo for 104 weeks (2 years) Total of all reporting groups
Overall Number of Baseline Participants 51 33 84
Hide Baseline Analysis Population Description
The safety population included all randomized participants who had received study medication. Participants in this population were used for all demographic and safety summaries. Participants were analyzed based on the treatment which they had received.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 51 participants 33 participants 84 participants
58.0  (6.04) 58.4  (7.71) 58.2  (6.70)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 51 participants 33 participants 84 participants
Female
24
  47.1%
17
  51.5%
41
  48.8%
Male
27
  52.9%
16
  48.5%
43
  51.2%
1.Primary Outcome
Title Change From Baseline to Week 104 in Trough Forced Expiratory Volume in 1 Second (FEV1)
Hide Description The analysis of the change from Baseline to Week 104 (last observation carried forward [LOCF]) in trough FEV1 is presented below.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The Intent-to-Treat (ITT) population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable High-resolution computed tomography (HRCT) scan.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 48 28
Mean (Standard Deviation)
Unit of Measure: L
-0.001  (0.2011) -0.083  (0.3241)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1761
Comments P-values are based on Analysis of Covariance (ANCOVA) model of the change FEV1 from baseline to the specified study week using treatment group and current smoking status as fixed effects and the baseline FEV1 value as a covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.0824
Confidence Interval (2-Sided) 95%
-0.0378 to 0.2025
Estimation Comments [Not Specified]
2.Primary Outcome
Title Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels
Hide Description 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.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 43 and 25 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 43 25
Mean (Standard Deviation)
Unit of Measure: Hounsfield unit/year
Right Upper (n= 43, 25) -2.639  (7.9744) 0.375  (7.1318)
Right Middle (n= 43, 25) -1.912  (6.0688) -0.831  (7.1709)
Right Lower (n= 43, 25) -1.884  (11.5558) 0.379  (11.0216)
Left Upper (n= 43, 25) -1.709  (9.8835) 0.686  (8.0797)
Left Lower (n= 43, 25) -0.713  (11.3439) 0.626  (11.4277)
Right Whole (n= 43, 25) -2.409  (7.3861) -0.225  (7.7509)
Left Whole (n= 43, 25) -0.882  (9.8780) 0.587  (8.9852)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Upper region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.139
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.904
Confidence Interval (2-Sided) 95%
-6.77 to 0.97
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Middle region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.460
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.210
Confidence Interval (2-Sided) 95%
-4.46 to 2.04
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Lower region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.457
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.176
Confidence Interval (2-Sided) 95%
-7.98 to 3.63
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Upper region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.362
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.167
Confidence Interval (2-Sided) 95%
-6.88 to 2.54
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Lower region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.670
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.225
Confidence Interval (2-Sided) 95%
-6.94 to 4.48
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Whole region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.244
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.218
Confidence Interval (2-Sided) 95%
-5.98 to 1.55
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Whole region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.574
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.374
Confidence Interval (2-Sided) 95%
-6.23 to 3.48
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Percent Change From Baseline in Trough FEV1 From Baseline to Week 104
Hide Description 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.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 28 and 18 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 28 18
Mean (Standard Deviation)
Unit of Measure: percentage change
-0.771  (14.4521) -7.071  (22.9110)
4.Secondary Outcome
Title Density Mask Score Based on Specified Thresholds Including -950 HU
Hide Description 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.
Time Frame Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 16 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 16
Mean (Standard Deviation)
Unit of Measure: Hounsfield unit
Right Upper (n= 23, 16) 0.57  (3.217) -0.38  (4.425)
Right Middle (n= 23, 16) 0.96  (2.992) -1.56  (4.980)
Right Lower (n= 23, 16) 1.17  (4.141) -0.75  (4.494)
Left Upper (n= 23, 16) 1.17  (3.713) -1.06  (4.823)
Left Lower (n= 23, 16) 1.22  (4.306) -1.06  (5.221)
Right Whole (n= 23, 16) 0.96  (3.483) -0.81  (4.151)
Left Whole (n= 23, 16) 1.09  (3.667) -1.00  (4.719)
Whole Lung (n= 23, 16) 1.04  (3.431) -1.00  (4.336)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Upper region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.436
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.97
Confidence Interval (2-Sided) 95%
-1.53 to 3.47
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Middle region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.067
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.31
Confidence Interval (2-Sided) 95%
-0.17 to 4.79
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Lower region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.163
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.97
Confidence Interval (2-Sided) 95%
-0.83 to 4.77
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Upper region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.102
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.27
Confidence Interval (2-Sided) 95%
-0.48 to 5.02
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Lower region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.162
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.11
Confidence Interval (2-Sided) 95%
-0.89 to 5.12
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Right Whole region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.160
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.78
Confidence Interval (2-Sided) 95%
-0.73 to 4.29
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Left Whole region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.122
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.08
Confidence Interval (2-Sided) 95%
-0.58 to 4.75
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of Whole Lung region of the Lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.106
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.05
Confidence Interval (2-Sided) 95%
-0.46 to 4.56
Estimation Comments [Not Specified]
5.Secondary Outcome
Title 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
Hide Description 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.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 46 and 26 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 46 26
Mean (Standard Deviation)
Unit of Measure: Hounsfield unit/year
-1.375  (7.909) 0.115  (8.166)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments LS Mean Difference between Tetomilast and Placebo at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.469
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.423
Confidence Interval (2-Sided) 95%
-5.32 to 2.48
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Observed Rate of Change in Emphysema From Baseline to Week 104
Hide Description 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).
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 16 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 16
Mean (Standard Deviation)
Unit of Measure: g/L
Right Upper (n= 23, 16) -0.64  (4.31) 0.58  (6.27)
Right Middle (n= 23, 16) -0.87  (3.96) 0.28  (5.77)
Right Lower (n= 23, 16) -0.53  (7.71) 0.39  (9.16)
Left Upper (n= 23, 16) -1.49  (5.66) 1.83  (7.04)
Left Lower (n= 23, 16) -0.62  (7.88) 0.42  (9.62)
Right Whole (n= 23, 16) -0.79  (5.23) 0.50  (6.78)
Left Whole (n= 23, 16) -0.95  (5.73) 1.14  (7.73)
Whole Lung (n= 23, 16) -0.85  (5.30) 0.74  (7.28)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right upper region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.519
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.07
Confidence Interval (2-Sided) 95%
-4.42 to 2.27
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right middle region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.463
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.05
Confidence Interval (2-Sided) 95%
-3.92 to 1.82
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right lower region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.598
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.40
Confidence Interval (2-Sided) 95%
-6.74 to 3.94
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left upper region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.142
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.94
Confidence Interval (2-Sided) 95%
-6.92 to 1.03
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left lower region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.757
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.83
Confidence Interval (2-Sided) 95%
-6.26 to 4.59
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right whole region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.500
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.27
Confidence Interval (2-Sided) 95%
-5.03 to 2.50
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left whole region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.353
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.93
Confidence Interval (2-Sided) 95%
-6.09 to 2.23
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of whole region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.438
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.52
Confidence Interval (2-Sided) 95%
-5.43 to 2.40
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Change From Baseline to Week 104 in Cumulative Frequency of HU
Hide Description 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.
Time Frame Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 16 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 16
Mean (Standard Deviation)
Unit of Measure: Hounsfield unit*hour
Right Upper (n= 23, 16) 4429363  (1696731) 4596228  (1012400)
Right Middle (n= 23, 16) 1474625  (409858) 1500073  (644286)
Right Lower (n= 23, 16) 4507375  (1302992) 4498652  (1703957)
Left Upper (n= 23, 16) 4818524  (1541192) 5105606  (1574676)
Left Lower (n= 23, 16) 4351407  (1677740) 4392819  (1256283)
Right Whole (n= 23, 16) 10411363  (2651975) 10594953  (2678348)
Left Whole (n= 23, 16) 9169931  (2630471) 9498425  (2471947)
Whole Lung (n= 23, 16) 19581293  (5212292) 20093377  (5022730)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right upper region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.220
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 351487
Confidence Interval (2-Sided) 95%
-219976 to 922951
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right middle region of the lung at Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.146
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 103036
Confidence Interval (2-Sided) 95%
-37651 to 243723
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right lower region of the lung at Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.322
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 247358
Confidence Interval (2-Sided) 95%
-252728 to 747444
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left upper region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.141
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 362384
Confidence Interval (2-Sided) 95%
-126518 to 851286
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left lower region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.325
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 294202
Confidence Interval (2-Sided) 95%
-303329 to 891733
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right whole region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.258
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 575882
Confidence Interval (2-Sided) 95%
-439692 to 1591457
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left whole region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.247
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 589373
Confidence Interval (2-Sided) 95%
-426928 to 1605673
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of whole lung region of the lung at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.251
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1156318
Confidence Interval (2-Sided) 95%
-855009 to 3167645
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV])
Hide Description Change from baseline in CT-derived lung volumes TLC and RV are presented in the below outcome data table.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 22 and 16 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 22 16
Mean (Standard Deviation)
Unit of Measure: mL
Right Upper (RV) (n= 22, 16) 31.4  (145.3) -64.3  (216.5)
Right Middle (RV) (n= 22, 16) -14.1  (65.7) -8.6  (63.6)
Right Lower (RV) (n= 22, 16) 18.1  (186.2) -49.3  (254.8)
Left Upper (RV) (n= 22, 16) 11.0  (153.8) -72.9  (212.9)
Left Lower (RV) (n= 22, 16) 13.0  (216.2) -52.8  (220.7)
Right Whole (RV) (n= 22, 16) 35.3  (350.7) -122.1  (504.5)
Left Whole (RV) (n= 22, 16) 23.8  (352.0) -125.6  (401.8)
Whole Lung (RV) (n= 22, 16) 59.4  (693.3) -247.8  (894.2)
Right Upper (TLC) (n= 22, 16) -0.7  (173.9) -52.3  (144.5)
Right Middle (TLC) (n= 22, 16) 3.7  (71.2) -6.1  (62.6)
Right Lower (TLC) (n= 22, 16) -12.5  (215.2) -18.1  (159.2)
Left Upper (TLC) (n= 22, 16) 1.0  (141.8) -59.1  (139.2)
Left Lower (TLC) (n= 22, 16) -6.9  (270.2) -35.8  (195.6)
Right Whole (TLC) (n= 22, 16) -9.2  (341.0) -76.3  (291.0)
Left Whole (TLC) (n= 22, 16) -6.1  (390.6) -95.1  (320.9)
Whole Lung (TLC) (n= 22, 16) -15.2  (711.3) -171.4  (584.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right upper lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.181
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 77.9
Confidence Interval (2-Sided) 95%
-38.0 to 193.8
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right middle lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.781
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.9
Confidence Interval (2-Sided) 95%
-48.8 to 36.9
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right lower lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.445
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 47.7
Confidence Interval (2-Sided) 95%
-77.8 to 173.2
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left upper lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.259
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 62.6
Confidence Interval (2-Sided) 95%
-48.1 to 173.2
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left lower lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.639
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 32.0
Confidence Interval (2-Sided) 95%
-105.6 to 169.6
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right whole lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.408
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 102.3
Confidence Interval (2-Sided) 95%
-145.9 to 350.5
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left whole lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.445
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 85.2
Confidence Interval (2-Sided) 95%
-138.8 to 309.2
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of whole lung region (RV) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.421
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 187.6
Confidence Interval (2-Sided) 95%
-279.6 to 654.8
Estimation Comments [Not Specified]
Show Statistical Analysis 9 Hide Statistical Analysis 9
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right upper lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.353
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 50.7
Confidence Interval (2-Sided) 95%
-58.5 to 159.9
Estimation Comments [Not Specified]
Show Statistical Analysis 10 Hide Statistical Analysis 10
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right middle lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.660
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 9.9
Confidence Interval (2-Sided) 95%
-35.3 to 55.0
Estimation Comments [Not Specified]
Show Statistical Analysis 11 Hide Statistical Analysis 11
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right lower lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.859
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 10.7
Confidence Interval (2-Sided) 95%
-110.7 to 132.1
Estimation Comments [Not Specified]
Show Statistical Analysis 12 Hide Statistical Analysis 12
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left upper lung region (TLC)at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.253
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 51.5
Confidence Interval (2-Sided) 95%
-38.4 to 141.4
Estimation Comments [Not Specified]
Show Statistical Analysis 13 Hide Statistical Analysis 13
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left lower lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.754
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 23.3
Confidence Interval (2-Sided) 95%
-126.0 to 172.6
Estimation Comments [Not Specified]
Show Statistical Analysis 14 Hide Statistical Analysis 14
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of right whole lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.546
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 62.2
Confidence Interval (2-Sided) 95%
-145.1 to 269.5
Estimation Comments [Not Specified]
Show Statistical Analysis 15 Hide Statistical Analysis 15
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of left whole lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.554
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 64.9
Confidence Interval (2-Sided) 95%
-155.5 to 285.3
Estimation Comments [Not Specified]
Show Statistical Analysis 16 Hide Statistical Analysis 16
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis of whole lung region (TLC) at Week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.524
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 132.2
Confidence Interval (2-Sided) 95%
-284.9 to 549.4
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change From Baseline to Week 104 in Trough RV/TLC
Hide Description Change from Baseline in Trough RV/TLC is presented in the below outcome data table.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were n= 21 and 14 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 21 14
Mean (Standard Deviation)
Unit of Measure: unitless
0.01  (0.12) 0.01  (0.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5843
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.01
Confidence Interval (2-Sided) 95%
-0.07 to 0.04
Estimation Comments [Not Specified]
10.Secondary Outcome
Title Change From Baseline to Week 104 in Trough Inspiratory Capacity
Hide Description Change from Baseline in Trough Inspiratory Capacity is presented in the below outcome data table.
Time Frame Baseline toWeek 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 25 and 14 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 25 14
Mean (Standard Deviation)
Unit of Measure: mL
0.074  (0.574) -0.225  (0.384)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1252
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.249
Confidence Interval (2-Sided) 95%
-0.073 to 0.571
Estimation Comments [Not Specified]
11.Secondary Outcome
Title Change From Baseline to Week 104 in Trough Functional Residual Capacity (FRCpleth)
Hide Description Change from baseline in trough FRCpleth is presented in the below outcome data table.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 15 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 15
Mean (Standard Deviation)
Unit of Measure: mL
-0.010  (1.0130) 0.029  (0.5290)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4661
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.1835
Confidence Interval (2-Sided) 95%
-0.6892 to 0.3221
Estimation Comments [Not Specified]
12.Secondary Outcome
Title Change From Baseline to Week 104 in Carbon Monoxide Diffusion Capacity (DLco)
Hide Description Change from Baseline in DLco is presented in the below outcome data table.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 15 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 15
Mean (Standard Deviation)
Unit of Measure: mmoL/min/kPA
0.021  (0.8485) -0.625  (1.6288)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.134
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.60
Confidence Interval (2-Sided) 95%
-0.19 to 1.40
Estimation Comments [Not Specified]
13.Secondary Outcome
Title Change From Baseline to Week 104 in Mean Specific Airway Resistance (sRaw) and Specific Conductance (sGaw)
Hide Description Change from baseline in sRaw and sGaw is presented in the below outcome data table.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 23 and 15 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 23 15
Mean (Standard Deviation)
Unit of Measure: kPa.sec
sRaw -0.29  (1.110) 0.47  (1.387)
sGaw 0.11  (0.584) -0.07  (0.293)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for sRaw
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.074
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.71
Confidence Interval (2-Sided) 95%
-1.50 to 0.07
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for sGaw
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.155
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.22
Confidence Interval (2-Sided) 95%
-0.09 to 0.52
Estimation Comments [Not Specified]
14.Secondary Outcome
Title Change From Baseline to Week 104 in 7-day Average Total Symptom Score of Dyspnea, Cough and Sputum
Hide Description 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).
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 13 and 9 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 13 9
Mean (Standard Deviation)
Unit of Measure: units on a scale
Mean prior daily breath symptoms (n= 13, 9) 0.13  (0.60) 0.20  (0.95)
Mean prior daily cough symptoms (n= 13, 9) 0.10  (0.40) -0.13  (1.13)
Mean prior daily sputum symptoms (n= 13, 9) 0.15  (0.74) 0.31  (1.07)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for mean prior daily breath symptoms
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.845
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.07
Confidence Interval (2-Sided) 95%
-0.77 to 0.64
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for mean prior daily cough symptoms
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.549
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.21
Confidence Interval (2-Sided) 95%
-0.52 to 0.94
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for mean prior daily sputum symptoms
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.717
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.14
Confidence Interval (2-Sided) 95%
-0.93 to 0.65
Estimation Comments [Not Specified]
15.Secondary Outcome
Title Change From Baseline to Week 104 in 7-day Mean Number of Actuations of Rescue Medications
Hide Description Participants recorded rescue medication use (albuterol and/or ipratropium bromide) in a rescue medication log.
Time Frame Baseline to Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan. The number of participants analyzed at Week 104 were N = 14 and 9 respectively.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 14 9
Mean (Standard Deviation)
Unit of Measure: number of puffs
-0.74  (1.57) -2.52  (3.82)
16.Secondary Outcome
Title Percentage of Participants With COPD Exacerbations by Group at Week 104
Hide Description 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).
Time Frame Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 48 28
Measure Type: Number
Unit of Measure: percentage of participants
Level I (Baseline) (n= 48, 28) 0.0 0.0
Level I (Week 104) (n= 23, 15) 4.3 6.7
Level II (Baseline) (n= 48, 28) 0.0 0.0
Level II (Week 104) (n= 23, 15) 8.7 6.7
Level III (Baseline) (n= 48, 28) 0.0 0.0
Level III (Week 104) (n= 23, 15) 8.7 0.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for level I (self management) at week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for level II (physician visit) at week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.0000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis for level III (hospital visit) at week 104.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.5092
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
17.Secondary Outcome
Title Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher)
Hide Description Percentage of participants experiencing a COPD exacerbation in a level 2 or higher are presented in the below outcome data table.
Time Frame Baseline and Week 104
Hide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all randomized participants with non-missing baseline data and at least one post-baseline trough FEV1 measurement or evaluable HRCT scan.
Arm/Group Title Tetomilast 50 mg Placebo
Hide Arm/Group Description:
Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.
Participants were administered matching placebo for 104 weeks (2 years)
Overall Number of Participants Analyzed 48 28
Measure Type: Number
Unit of Measure: percentage of participants
Level 2 or Higher (Baseline) 0.0 0.0
Level 1 or No Exacerbation (Baseline) 100.0 100.0
Level 2 or Higher (Week 104) 8.3 3.6
Level 1 or No Exacerbation (Week 104) 39.6 50.0
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tetomilast 50 mg, Placebo
Comments Statistical analysis at Week 104
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.630
Comments Fisher’s Exact test was used to determine whether the tetomilast and placebo groups differ in the proportion of participants who experienced Level 2 or higher COPD exacerbations during the study.
Method Fisher Exact
Comments [Not Specified]
Time Frame Adverse events were reported from the signing of the informed consent, throughout the 104 week treatment period until the follow-up visit of 14 (+2) days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Tetomilast 25 mg Placebo
Hide Arm/Group Description Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks. Participants were administered matching placebo for 104 weeks (2 years)
All-Cause Mortality
Tetomilast 25 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Tetomilast 25 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   13/51 (25.49%)   12/33 (36.36%) 
Blood and lymphatic system disorders     
Anaemia * 1  0/51 (0.00%)  1/33 (3.03%) 
Cardiac disorders     
Angina unstable * 1  0/51 (0.00%)  1/33 (3.03%) 
Coronary artery stenosis * 1  0/51 (0.00%)  1/33 (3.03%) 
Gastrointestinal disorders     
Colitis * 1  0/51 (0.00%)  2/33 (6.06%) 
Abdominal pain * 1  1/51 (1.96%)  0/33 (0.00%) 
Abdominal pain upper * 1  0/51 (0.00%)  1/33 (3.03%) 
Duodenal ulcer * 1  1/51 (1.96%)  0/33 (0.00%) 
Duodenal ulcer haemorrhage * 1  0/51 (0.00%)  1/33 (3.03%) 
Dysphagia * 1  1/51 (1.96%)  0/33 (0.00%) 
Erosive duodenitis * 1  1/51 (1.96%)  0/33 (0.00%) 
Ileus * 1  0/51 (0.00%)  1/33 (3.03%) 
Inguinal hernia, obstructive * 1  1/51 (1.96%)  0/33 (0.00%) 
Large intestinal stenosis * 1  0/51 (0.00%)  1/33 (3.03%) 
Melaena * 1  1/51 (1.96%)  0/33 (0.00%) 
Nausea * 1  1/51 (1.96%)  0/33 (0.00%) 
Vomiting * 1  1/51 (1.96%)  0/33 (0.00%) 
General disorders     
Non-cardiac chest pain * 1  2/51 (3.92%)  0/33 (0.00%) 
Hepatobiliary disorders     
Bile duct stenosis * 1  1/51 (1.96%)  0/33 (0.00%) 
Biliary colic * 1  0/51 (0.00%)  1/33 (3.03%) 
Infections and infestations     
Pneumonia * 1  2/51 (3.92%)  3/33 (9.09%) 
Lobar Pneumonia * 1  2/51 (3.92%)  0/33 (0.00%) 
Cellulitis * 1  0/51 (0.00%)  1/33 (3.03%) 
Clostridium difficile colitis * 1  1/51 (1.96%)  0/33 (0.00%) 
Colostomy infection * 1  0/51 (0.00%)  1/33 (3.03%) 
Corona virus infection * 1  0/51 (0.00%)  1/33 (3.03%) 
Diverticulitis * 1  0/51 (0.00%)  1/33 (3.03%) 
Influenza * 1  1/51 (1.96%)  0/33 (0.00%) 
Injury, poisoning and procedural complications     
Carotid artery restenosis * 1  0/51 (0.00%)  1/33 (3.03%) 
Procedural headache * 1  1/51 (1.96%)  0/33 (0.00%) 
Toxicity to various agents * 1  0/51 (0.00%)  1/33 (3.03%) 
Investigations     
Hepatic enzyme increased * 1  0/51 (0.00%)  1/33 (3.03%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung adenocarcinoma * 1  0/51 (0.00%)  1/33 (3.03%) 
Lung neoplasm malignant * 1  1/51 (1.96%)  0/33 (0.00%) 
Metastatic neoplasm * 1  1/51 (1.96%)  0/33 (0.00%) 
Nervous system disorders     
Ischaemic cerebral infarction * 1  1/51 (1.96%)  0/33 (0.00%) 
Psychiatric disorders     
Psychotic disorder * 1  0/51 (0.00%)  1/33 (3.03%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstrutive pulmonary disease * 1  6/51 (11.76%)  4/33 (12.12%) 
Dyspnoea * 1  1/51 (1.96%)  1/33 (3.03%) 
Respiratory failure * 1  2/51 (3.92%)  0/33 (0.00%) 
Atelectasis * 1  1/51 (1.96%)  0/33 (0.00%) 
Pleural effusion * 1  1/51 (1.96%)  0/33 (0.00%) 
Pneumothorax * 1  1/51 (1.96%)  0/33 (0.00%) 
Pulmonary embolism * 1  1/51 (1.96%)  0/33 (0.00%) 
Vascular disorders     
Aortic aneurysm * 1  1/51 (1.96%)  0/33 (0.00%) 
Deep vein thrombosis * 1  1/51 (1.96%)  0/33 (0.00%) 
Peripheral arterial occlusive disease * 1  1/51 (1.96%)  0/33 (0.00%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tetomilast 25 mg Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   30/51 (58.82%)   23/33 (69.70%) 
Blood and lymphatic system disorders     
Leukocytosis * 1  0/51 (0.00%)  2/33 (6.06%) 
Cardiac disorders     
Palpitations * 1  0/51 (0.00%)  2/33 (6.06%) 
Gastrointestinal disorders     
Abdominal pain * 1  3/51 (5.88%)  2/33 (6.06%) 
Constipation * 1  1/51 (1.96%)  2/33 (6.06%) 
Diarrhoea * 1  5/51 (9.80%)  2/33 (6.06%) 
Gastritis * 1  3/51 (5.88%)  0/33 (0.00%) 
Gastrooesophageal reflux disease * 1  1/51 (1.96%)  2/33 (6.06%) 
Nausea * 1  3/51 (5.88%)  1/33 (3.03%) 
General disorders     
Pyrexia * 1  0/51 (0.00%)  2/33 (6.06%) 
Infections and infestations     
Bronchitis * 1  5/51 (9.80%)  6/33 (18.18%) 
Gastroenteritis viral * 1  0/51 (0.00%)  2/33 (6.06%) 
Sinusitis * 1  2/51 (3.92%)  3/33 (9.09%) 
Upper respiratory tract infection * 1  5/51 (9.80%)  3/33 (9.09%) 
Urinary tract infection * 1  3/51 (5.88%)  3/33 (9.09%) 
Investigations     
Weight decreased * 1  0/51 (0.00%)  2/33 (6.06%) 
Metabolism and nutrition disorders     
Dehydration * 1  0/51 (0.00%)  3/33 (9.09%) 
Hypokalemia * 1  0/51 (0.00%)  2/33 (6.06%) 
Hyponatraemia * 1  0/51 (0.00%)  2/33 (6.06%) 
Nervous system disorders     
Headache * 1  1/51 (1.96%)  2/33 (6.06%) 
Psychiatric disorders     
Anxiety * 1  2/51 (3.92%)  2/33 (6.06%) 
Reproductive system and breast disorders     
Benign prostatic hyperplasia * 1  3/51 (5.88%)  0/33 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstrictive pulmonary disease * 1  16/51 (31.37%)  13/33 (39.39%) 
Cough * 1  4/51 (7.84%)  3/33 (9.09%) 
Dyspnoea * 1  0/51 (0.00%)  2/33 (6.06%) 
Respiratory tract congestion * 1  0/51 (0.00%)  2/33 (6.06%) 
Skin and subcutaneous tissue disorders     
Ecchymosis * 1  0/51 (0.00%)  2/33 (6.06%) 
Vascular disorders     
Hypertension * 1  3/51 (5.88%)  2/33 (6.06%) 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.0)
This trial was terminated early, not due to a safety concern, but due to a business decision to cease development of the tetolimast clinical program.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Global Medical Affairs
Organization: Otsuka Pharmaceutical Development and Commercialization, Inc.
Phone: 800 562-3974
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Responsible Party: Otsuka Pharmaceutical Development & Commercialization, Inc.
ClinicalTrials.gov Identifier: NCT00874497     History of Changes
Other Study ID Numbers: 197-08-250
First Submitted: March 31, 2009
First Posted: April 2, 2009
Results First Submitted: August 23, 2016
Results First Posted: April 17, 2017
Last Update Posted: April 17, 2017