Trial Outcomes & Findings for Pilot Study of Tetomilast in Chronic Obstructive Pulmonary Disease (COPD) Associated With Emphysema (NCT NCT00874497)

Last Updated: 2017-04-17

Results Overview

The analysis of the change from Baseline to Week 104 (last observation carried forward \[LOCF\]) in trough FEV1 is presented below.

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

84 participants

Primary outcome timeframe

Baseline to Week 104

Results posted on

2017-04-17

Participant Flow

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.

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.

Participant milestones

Participant milestones
Measure	Tetomilast 50 mg Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo Participants were administered matching placebo for 104 weeks (2 years)
Overall Study STARTED	51	33
Overall Study COMPLETED	23	15
Overall Study NOT COMPLETED	28	18

Reasons for withdrawal

Reasons for withdrawal
Measure	Tetomilast 50 mg Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo Participants were administered matching placebo for 104 weeks (2 years)
Overall Study Lost to Follow-up	2	4
Overall Study Adverse Event	9	4
Overall Study Sponsor Discontinued Trial	7	3
Overall Study Met Withdrawal Criteria	4	2
Overall Study Physician Decision	1	1
Overall Study Withdrawal by Subject	5	4

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tetomilast 50 mg n=51 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=33 Participants Participants were administered matching placebo for 104 weeks (2 years)	Total n=84 Participants Total of all reporting groups
Age, Continuous	58.0 years STANDARD_DEVIATION 6.04 • n=5 Participants	58.4 years STANDARD_DEVIATION 7.71 • n=7 Participants	58.2 years STANDARD_DEVIATION 6.70 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants	17 Participants n=7 Participants	41 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	16 Participants n=7 Participants	43 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline to Week 104

Population: 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.

The analysis of the change from Baseline to Week 104 (last observation carried forward \[LOCF\]) in trough FEV1 is presented below.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=48 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=28 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Trough Forced Expiratory Volume in 1 Second (FEV1)	-0.001 L Standard Deviation 0.2011	-0.083 L Standard Deviation 0.3241

PRIMARY outcome

Timeframe: Baseline to Week 104

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=43 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=25 Participants Participants were administered matching placebo for 104 weeks (2 years)
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Right Upper (n= 43, 25)	-2.639 Hounsfield unit/year Standard Deviation 7.9744	0.375 Hounsfield unit/year Standard Deviation 7.1318
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Right Middle (n= 43, 25)	-1.912 Hounsfield unit/year Standard Deviation 6.0688	-0.831 Hounsfield unit/year Standard Deviation 7.1709
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Right Lower (n= 43, 25)	-1.884 Hounsfield unit/year Standard Deviation 11.5558	0.379 Hounsfield unit/year Standard Deviation 11.0216
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Left Upper (n= 43, 25)	-1.709 Hounsfield unit/year Standard Deviation 9.8835	0.686 Hounsfield unit/year Standard Deviation 8.0797
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Left Lower (n= 43, 25)	-0.713 Hounsfield unit/year Standard Deviation 11.3439	0.626 Hounsfield unit/year Standard Deviation 11.4277
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Right Whole (n= 43, 25)	-2.409 Hounsfield unit/year Standard Deviation 7.3861	-0.225 Hounsfield unit/year Standard Deviation 7.7509
Rate of Change From Baseline to Week 104 in 20th Percentile of Lung Density Voxels Left Whole (n= 43, 25)	-0.882 Hounsfield unit/year Standard Deviation 9.8780	0.587 Hounsfield unit/year Standard Deviation 8.9852

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=28 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=18 Participants Participants were administered matching placebo for 104 weeks (2 years)
Percent Change From Baseline in Trough FEV1 From Baseline to Week 104	-0.771 percentage change Standard Deviation 14.4521	-7.071 percentage change Standard Deviation 22.9110

SECONDARY outcome

Timeframe: Baseline and Week 104

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.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=16 Participants Participants were administered matching placebo for 104 weeks (2 years)
Density Mask Score Based on Specified Thresholds Including -950 HU Right Upper (n= 23, 16)	0.57 Hounsfield unit Standard Deviation 3.217	-0.38 Hounsfield unit Standard Deviation 4.425
Density Mask Score Based on Specified Thresholds Including -950 HU Right Middle (n= 23, 16)	0.96 Hounsfield unit Standard Deviation 2.992	-1.56 Hounsfield unit Standard Deviation 4.980
Density Mask Score Based on Specified Thresholds Including -950 HU Right Lower (n= 23, 16)	1.17 Hounsfield unit Standard Deviation 4.141	-0.75 Hounsfield unit Standard Deviation 4.494
Density Mask Score Based on Specified Thresholds Including -950 HU Left Upper (n= 23, 16)	1.17 Hounsfield unit Standard Deviation 3.713	-1.06 Hounsfield unit Standard Deviation 4.823
Density Mask Score Based on Specified Thresholds Including -950 HU Left Lower (n= 23, 16)	1.22 Hounsfield unit Standard Deviation 4.306	-1.06 Hounsfield unit Standard Deviation 5.221
Density Mask Score Based on Specified Thresholds Including -950 HU Right Whole (n= 23, 16)	0.96 Hounsfield unit Standard Deviation 3.483	-0.81 Hounsfield unit Standard Deviation 4.151
Density Mask Score Based on Specified Thresholds Including -950 HU Left Whole (n= 23, 16)	1.09 Hounsfield unit Standard Deviation 3.667	-1.00 Hounsfield unit Standard Deviation 4.719
Density Mask Score Based on Specified Thresholds Including -950 HU Whole Lung (n= 23, 16)	1.04 Hounsfield unit Standard Deviation 3.431	-1.00 Hounsfield unit Standard Deviation 4.336

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=46 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=26 Participants Participants were administered matching placebo for 104 weeks (2 years)
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	-1.375 Hounsfield unit/year Standard Deviation 7.909	0.115 Hounsfield unit/year Standard Deviation 8.166

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=16 Participants Participants were administered matching placebo for 104 weeks (2 years)
Observed Rate of Change in Emphysema From Baseline to Week 104 Right Upper (n= 23, 16)	-0.64 g/L Standard Deviation 4.31	0.58 g/L Standard Deviation 6.27
Observed Rate of Change in Emphysema From Baseline to Week 104 Right Middle (n= 23, 16)	-0.87 g/L Standard Deviation 3.96	0.28 g/L Standard Deviation 5.77
Observed Rate of Change in Emphysema From Baseline to Week 104 Right Lower (n= 23, 16)	-0.53 g/L Standard Deviation 7.71	0.39 g/L Standard Deviation 9.16
Observed Rate of Change in Emphysema From Baseline to Week 104 Left Upper (n= 23, 16)	-1.49 g/L Standard Deviation 5.66	1.83 g/L Standard Deviation 7.04
Observed Rate of Change in Emphysema From Baseline to Week 104 Left Lower (n= 23, 16)	-0.62 g/L Standard Deviation 7.88	0.42 g/L Standard Deviation 9.62
Observed Rate of Change in Emphysema From Baseline to Week 104 Right Whole (n= 23, 16)	-0.79 g/L Standard Deviation 5.23	0.50 g/L Standard Deviation 6.78
Observed Rate of Change in Emphysema From Baseline to Week 104 Left Whole (n= 23, 16)	-0.95 g/L Standard Deviation 5.73	1.14 g/L Standard Deviation 7.73
Observed Rate of Change in Emphysema From Baseline to Week 104 Whole Lung (n= 23, 16)	-0.85 g/L Standard Deviation 5.30	0.74 g/L Standard Deviation 7.28

SECONDARY outcome

Timeframe: Baseline and Week 104

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.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=16 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Cumulative Frequency of HU Right Upper (n= 23, 16)	4429363 Hounsfield unit*hour Standard Deviation 1696731	4596228 Hounsfield unit*hour Standard Deviation 1012400
Change From Baseline to Week 104 in Cumulative Frequency of HU Right Middle (n= 23, 16)	1474625 Hounsfield unit*hour Standard Deviation 409858	1500073 Hounsfield unit*hour Standard Deviation 644286
Change From Baseline to Week 104 in Cumulative Frequency of HU Right Lower (n= 23, 16)	4507375 Hounsfield unit*hour Standard Deviation 1302992	4498652 Hounsfield unit*hour Standard Deviation 1703957
Change From Baseline to Week 104 in Cumulative Frequency of HU Left Upper (n= 23, 16)	4818524 Hounsfield unit*hour Standard Deviation 1541192	5105606 Hounsfield unit*hour Standard Deviation 1574676
Change From Baseline to Week 104 in Cumulative Frequency of HU Left Lower (n= 23, 16)	4351407 Hounsfield unit*hour Standard Deviation 1677740	4392819 Hounsfield unit*hour Standard Deviation 1256283
Change From Baseline to Week 104 in Cumulative Frequency of HU Right Whole (n= 23, 16)	10411363 Hounsfield unit*hour Standard Deviation 2651975	10594953 Hounsfield unit*hour Standard Deviation 2678348
Change From Baseline to Week 104 in Cumulative Frequency of HU Left Whole (n= 23, 16)	9169931 Hounsfield unit*hour Standard Deviation 2630471	9498425 Hounsfield unit*hour Standard Deviation 2471947
Change From Baseline to Week 104 in Cumulative Frequency of HU Whole Lung (n= 23, 16)	19581293 Hounsfield unit*hour Standard Deviation 5212292	20093377 Hounsfield unit*hour Standard Deviation 5022730

SECONDARY outcome

Timeframe: Baseline to Week 104

Change from baseline in CT-derived lung volumes TLC and RV are presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=22 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=16 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Upper (RV) (n= 22, 16)	31.4 mL Standard Deviation 145.3	-64.3 mL Standard Deviation 216.5
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Middle (RV) (n= 22, 16)	-14.1 mL Standard Deviation 65.7	-8.6 mL Standard Deviation 63.6
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Lower (RV) (n= 22, 16)	18.1 mL Standard Deviation 186.2	-49.3 mL Standard Deviation 254.8
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Upper (RV) (n= 22, 16)	11.0 mL Standard Deviation 153.8	-72.9 mL Standard Deviation 212.9
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Lower (RV) (n= 22, 16)	13.0 mL Standard Deviation 216.2	-52.8 mL Standard Deviation 220.7
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Whole (RV) (n= 22, 16)	35.3 mL Standard Deviation 350.7	-122.1 mL Standard Deviation 504.5
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Whole (RV) (n= 22, 16)	23.8 mL Standard Deviation 352.0	-125.6 mL Standard Deviation 401.8
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Whole Lung (RV) (n= 22, 16)	59.4 mL Standard Deviation 693.3	-247.8 mL Standard Deviation 894.2
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Upper (TLC) (n= 22, 16)	-0.7 mL Standard Deviation 173.9	-52.3 mL Standard Deviation 144.5
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Middle (TLC) (n= 22, 16)	3.7 mL Standard Deviation 71.2	-6.1 mL Standard Deviation 62.6
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Lower (TLC) (n= 22, 16)	-12.5 mL Standard Deviation 215.2	-18.1 mL Standard Deviation 159.2
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Upper (TLC) (n= 22, 16)	1.0 mL Standard Deviation 141.8	-59.1 mL Standard Deviation 139.2
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Lower (TLC) (n= 22, 16)	-6.9 mL Standard Deviation 270.2	-35.8 mL Standard Deviation 195.6
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Right Whole (TLC) (n= 22, 16)	-9.2 mL Standard Deviation 341.0	-76.3 mL Standard Deviation 291.0
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Left Whole (TLC) (n= 22, 16)	-6.1 mL Standard Deviation 390.6	-95.1 mL Standard Deviation 320.9
Change From Baseline to Week 104 in Computed Tomography (CT) - Derived Lung Volumes (Total Lung Capacity [TLC] and Residual Volume [RV]) Whole Lung (TLC) (n= 22, 16)	-15.2 mL Standard Deviation 711.3	-171.4 mL Standard Deviation 584.4

SECONDARY outcome

Timeframe: Baseline to Week 104

Change from Baseline in Trough RV/TLC is presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=21 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=14 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Trough RV/TLC	0.01 unitless Standard Deviation 0.12	0.01 unitless Standard Deviation 0.07

SECONDARY outcome

Timeframe: Baseline toWeek 104

Change from Baseline in Trough Inspiratory Capacity is presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=25 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=14 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Trough Inspiratory Capacity	0.074 mL Standard Deviation 0.574	-0.225 mL Standard Deviation 0.384

SECONDARY outcome

Timeframe: Baseline to Week 104

Change from baseline in trough FRCpleth is presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=15 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Trough Functional Residual Capacity (FRCpleth)	-0.010 mL Standard Deviation 1.0130	0.029 mL Standard Deviation 0.5290

SECONDARY outcome

Timeframe: Baseline to Week 104

Change from Baseline in DLco is presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=15 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Carbon Monoxide Diffusion Capacity (DLco)	0.021 mmoL/min/kPA Standard Deviation 0.8485	-0.625 mmoL/min/kPA Standard Deviation 1.6288

SECONDARY outcome

Timeframe: Baseline to Week 104

Change from baseline in sRaw and sGaw is presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=23 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=15 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in Mean Specific Airway Resistance (sRaw) and Specific Conductance (sGaw) sRaw	-0.29 kPa.sec Standard Deviation 1.110	0.47 kPa.sec Standard Deviation 1.387
Change From Baseline to Week 104 in Mean Specific Airway Resistance (sRaw) and Specific Conductance (sGaw) sGaw	0.11 kPa.sec Standard Deviation 0.584	-0.07 kPa.sec Standard Deviation 0.293

SECONDARY outcome

Timeframe: Baseline to Week 104

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).

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=13 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=9 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in 7-day Average Total Symptom Score of Dyspnea, Cough and Sputum Mean prior daily breath symptoms (n= 13, 9)	0.13 units on a scale Standard Deviation 0.60	0.20 units on a scale Standard Deviation 0.95
Change From Baseline to Week 104 in 7-day Average Total Symptom Score of Dyspnea, Cough and Sputum Mean prior daily cough symptoms (n= 13, 9)	0.10 units on a scale Standard Deviation 0.40	-0.13 units on a scale Standard Deviation 1.13
Change From Baseline to Week 104 in 7-day Average Total Symptom Score of Dyspnea, Cough and Sputum Mean prior daily sputum symptoms (n= 13, 9)	0.15 units on a scale Standard Deviation 0.74	0.31 units on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: Baseline to Week 104

Participants recorded rescue medication use (albuterol and/or ipratropium bromide) in a rescue medication log.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=14 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=9 Participants Participants were administered matching placebo for 104 weeks (2 years)
Change From Baseline to Week 104 in 7-day Mean Number of Actuations of Rescue Medications	-0.74 number of puffs Standard Deviation 1.57	-2.52 number of puffs Standard Deviation 3.82

SECONDARY outcome

Timeframe: Baseline and Week 104

Population: 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.

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).

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=48 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=28 Participants Participants were administered matching placebo for 104 weeks (2 years)
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level I (Baseline) (n= 48, 28)	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level I (Week 104) (n= 23, 15)	4.3 percentage of participants	6.7 percentage of participants
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level II (Baseline) (n= 48, 28)	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level II (Week 104) (n= 23, 15)	8.7 percentage of participants	6.7 percentage of participants
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level III (Baseline) (n= 48, 28)	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants With COPD Exacerbations by Group at Week 104 Level III (Week 104) (n= 23, 15)	8.7 percentage of participants	0.0 percentage of participants

SECONDARY outcome

Timeframe: Baseline and Week 104

Population: 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.

Percentage of participants experiencing a COPD exacerbation in a level 2 or higher are presented in the below outcome data table.

Outcome measures

Outcome measures
Measure	Tetomilast 50 mg n=48 Participants Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=28 Participants Participants were administered matching placebo for 104 weeks (2 years)
Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher) Level 2 or Higher (Baseline)	0.0 percentage of participants	0.0 percentage of participants
Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher) Level 1 or No Exacerbation (Baseline)	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher) Level 2 or Higher (Week 104)	8.3 percentage of participants	3.6 percentage of participants
Percentage of Participants Experiencing a COPD Exacerbation (Level 2 or Higher) Level 1 or No Exacerbation (Week 104)	39.6 percentage of participants	50.0 percentage of participants

Adverse Events

Tetomilast 25 mg

Serious events: 13 serious events

Other events: 30 other events

Deaths: 0 deaths

Placebo

Serious events: 12 serious events

Other events: 23 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Global Medical Affairs

Otsuka Pharmaceutical Development and Commercialization, Inc.

Phone: 800 562-3974

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	Tetomilast 25 mg n=51 participants at risk Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=33 participants at risk Participants were administered matching placebo for 104 weeks (2 years)
Infections and infestations Pneumonia	3.9% 2/51 • 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.	9.1% 3/33 • 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.
Infections and infestations Lobar Pneumonia	3.9% 2/51 • 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.	0.00% 0/33 • 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.
Infections and infestations Cellulitis	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Infections and infestations Clostridium difficile colitis	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Infections and infestations Colostomy infection	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Infections and infestations Corona virus infection	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Infections and infestations Diverticulitis	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Infections and infestations Influenza	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstrutive pulmonary disease	11.8% 6/51 • 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.	12.1% 4/33 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	2.0% 1/51 • 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.	3.0% 1/33 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory failure	3.9% 2/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Atelectasis	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Pleural effusion	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Pneumothorax	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Colitis	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Abdominal pain	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Abdominal pain upper	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Gastrointestinal disorders Duodenal ulcer	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Duodenal ulcer haemorrhage	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Gastrointestinal disorders Dysphagia	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Erosive duodenitis	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Ileus	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Gastrointestinal disorders Inguinal hernia, obstructive	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Large intestinal stenosis	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Gastrointestinal disorders Melaena	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Nausea	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Vomiting	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Injury, poisoning and procedural complications Carotid artery restenosis	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Injury, poisoning and procedural complications Procedural headache	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastatic neoplasm	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Cardiac disorders Angina unstable	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Cardiac disorders Coronary artery stenosis	0.00% 0/51 • 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.	3.0% 1/33 • 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.
General disorders Non-cardiac chest pain	3.9% 2/51 • 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.	0.00% 0/33 • 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.
Hepatobiliary disorders Bile duct stenosis	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Hepatobiliary disorders Biliary colic	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Vascular disorders Aortic aneurysm	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Vascular disorders Deep vein thrombosis	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Vascular disorders Peripheral arterial occlusive disease	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Blood and lymphatic system disorders Anaemia	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Investigations Hepatic enzyme increased	0.00% 0/51 • 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.	3.0% 1/33 • 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.
Nervous system disorders Ischaemic cerebral infarction	2.0% 1/51 • 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.	0.00% 0/33 • 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.
Psychiatric disorders Psychotic disorder	0.00% 0/51 • 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.	3.0% 1/33 • 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.

Measure	Tetomilast 25 mg n=51 participants at risk Participants were administered oral tetomilast 25 milligram (mg) once daily for 2 weeks followed by 50 mg once daily for 102 weeks.	Placebo n=33 participants at risk Participants were administered matching placebo for 104 weeks (2 years)
Blood and lymphatic system disorders Leukocytosis	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Cardiac disorders Palpitations	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Abdominal pain	5.9% 3/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Constipation	2.0% 1/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Diarrhoea	9.8% 5/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Gastritis	5.9% 3/51 • 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.	0.00% 0/33 • 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.
Gastrointestinal disorders Gastrooesophageal reflux disease	2.0% 1/51 • 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.	6.1% 2/33 • 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.
Gastrointestinal disorders Nausea	5.9% 3/51 • 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.	3.0% 1/33 • 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.
General disorders Pyrexia	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Infections and infestations Bronchitis	9.8% 5/51 • 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.	18.2% 6/33 • 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.
Infections and infestations Gastroenteritis viral	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Infections and infestations Sinusitis	3.9% 2/51 • 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.	9.1% 3/33 • 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.
Infections and infestations Upper respiratory tract infection	9.8% 5/51 • 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.	9.1% 3/33 • 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.
Infections and infestations Urinary tract infection	5.9% 3/51 • 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.	9.1% 3/33 • 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.
Investigations Weight decreased	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Metabolism and nutrition disorders Dehydration	0.00% 0/51 • 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.	9.1% 3/33 • 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.
Metabolism and nutrition disorders Hypokalemia	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Nervous system disorders Headache	2.0% 1/51 • 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.	6.1% 2/33 • 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.
Psychiatric disorders Anxiety	3.9% 2/51 • 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.	6.1% 2/33 • 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.
Reproductive system and breast disorders Benign prostatic hyperplasia	5.9% 3/51 • 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.	0.00% 0/33 • 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.
Respiratory, thoracic and mediastinal disorders Chronic obstrictive pulmonary disease	31.4% 16/51 • 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.	39.4% 13/33 • 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.
Respiratory, thoracic and mediastinal disorders Cough	7.8% 4/51 • 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.	9.1% 3/33 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Respiratory, thoracic and mediastinal disorders Respiratory tract congestion	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Skin and subcutaneous tissue disorders Ecchymosis	0.00% 0/51 • 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.	6.1% 2/33 • 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.
Vascular disorders Hypertension	5.9% 3/51 • 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.	6.1% 2/33 • 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.