Trial Outcomes & Findings for Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo in 1 to 5 Year Old Patients With Persistent Asthma (NCT NCT01634113)

Last Updated: 2015-06-23

Results Overview

Change from baseline in the weekly mean combined daytime asthma symptom score as assessed by the Paediatric Asthma Caregivers Diary (PACD) in the last week of the 12 week treatment period. The PACD is a diary designed to evaluate daily asthma symptoms in children aged 2-5 years. The diary consists of three questions to be answered each morning, when the child wakes up, and seven questions to be answered each evening, right after the child goes to bed for the night. A week was defined as 7 days. The combined daytime score is the average of scores from questions 4 - 7 in the diary which are questions regarding severity of cough, wheezing, trouble breathing and interference with activities, scores for each question range from 0 (best) to 5 (worst). The week 12 weekly mean is the mean of the responses for each day averaged over the 7 days in week 12, so combined daytime asthma symptom scores also range from 0 (best) to 5 (worst). The measured values presented are adjusted means.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

102 participants

Primary outcome timeframe

Baseline and 12 weeks

Results posted on

2015-06-23

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Respimat Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Overall Study STARTED	34	36	32
Overall Study COMPLETED	34	36	31
Overall Study NOT COMPLETED	0	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Respimat Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Overall Study Not treated	0	0	1

Baseline Characteristics

Evaluation of Tiotropium 2.5 and 5 mcg Once Daily Delivered Via the Respimat® Inhaler Compared to Placebo in 1 to 5 Year Old Patients With Persistent Asthma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Respimat n=34 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=31 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.	Total n=101 Participants Total of all reporting groups
Age, Continuous	3.2 years STANDARD_DEVIATION 1.4 • n=5 Participants	3.1 years STANDARD_DEVIATION 1.5 • n=7 Participants	3.1 years STANDARD_DEVIATION 1.3 • n=5 Participants	3.1 years STANDARD_DEVIATION 1.4 • n=4 Participants
Sex: Female, Male Female	13 Participants n=5 Participants	17 Participants n=7 Participants	10 Participants n=5 Participants	40 Participants n=4 Participants
Sex: Female, Male Male	21 Participants n=5 Participants	19 Participants n=7 Participants	21 Participants n=5 Participants	61 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set, which included all randomised patients who received at least one dose of trial medication, including patients with available endpoint data at week 12. Missing data in a week was imputed by the available data from the patient during that week, for weeks where data was completely missing no imputation was employed.

Outcome measures

Outcome measures
Measure	Placebo Respimat n=34 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=30 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Weekly Mean Combined Daytime Asthma Symptom Score	-0.456 units on a scale Standard Error 0.084	-0.535 units on a scale Standard Error 0.082	-0.504 units on a scale Standard Error 0.089

PRIMARY outcome

Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline in peak Forced expiratory volume in 1 second within the first 3 hours post dosing (FEV1 peak (0-3h)) measured at week 12

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
FEV1 Peak (0-3h) Change From Baseline	0.158 Litres Standard Deviation 0.026	0.130 Litres Standard Deviation 0.125	0.145 Litres Standard Deviation 0.078

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set, including patients with available endpoint data at week 12. Missing data in a week was imputed by the available data from the patient during that week, for weeks where data was completely missing no imputation was employed.

Change from baseline in the weekly mean overnight asthma symptom score response as assessed by the PACD in the last week of the 12 week treatment period. The overnight score is the score from the following question in the PACD, "How much did your child cough last night after your child was put to bed for the night until he/she awoke this morning?". This endpoint was determined only for patients with 2 or more nights with symptoms per week during the baseline period. In this case, the baseline period is the 7 days used to derive the baseline value. A patient has a night with symptoms if the question was answered with scores 1, 2, 3, 4 or 5 or the patient received β-Agonist at least one time since he/she went to bed. A week was defined as 7 days. Scores range from 0 (best) to 4 (worst), a value of 5 indicates severity of symptoms is unknown. The measured values presented are adjusted means

Outcome measures

Outcome measures
Measure	Placebo Respimat n=31 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=31 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=28 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Weekly Mean Overnight Asthma Symptom Score Response	-0.671 units on a scale Standard Error 0.110	-0.588 units on a scale Standard Error 0.111	-0.655 units on a scale Standard Error 0.116

SECONDARY outcome

Timeframe: 12 weeks

Weekly Percentage of days without asthma symptoms at week 12. A day without asthma symptoms was defined as a day during which the patient experienced no asthma symptoms, did not use rescue medication (salbutamol/albuterol) and had no asthma exacerbation/worsening requiring systemic corticosteroids, or unscheduled visits to a doctor's office, emergency department, or hospital. A week was defined as 7 days. The measured values presented are adjusted means

Outcome measures

Outcome measures
Measure	Placebo Respimat n=34 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=30 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Weekly Percentage of Days Without Asthma Symptoms	53.151 percentage of days Standard Error 7.405	55.401 percentage of days Standard Error 7.181	50.654 percentage of days Standard Error 7.873

SECONDARY outcome

Timeframe: 12 weeks

Weekly percentage of days with use of salbutamol (albuterol) rescue medication at week 12. A week was defined as 7 days.

Outcome measures

Outcome measures
Measure	Placebo Respimat n=34 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=30 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Weekly Percentage of Days With Use of Salbutamol (Albuterol) Rescue Medication	24.94 percentage of days Standard Deviation 36.80	24.23 percentage of days Standard Deviation 36.86	24.88 percentage of days Standard Deviation 38.45

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Change from baseline in the weekly mean nighttime awakenings due to asthma symptoms as assessed by the PACD, in the last week of the 12 week treatment period. The weekly mean was calculated as the average of the weekly scores for the question "Did your child wake up during the night due to his/her asthma?" The question was answered on a 5-point verbal rating scale, with scores ranging from 1 (did not wake up) to 5 (was awake all night). A week was defined as 7 days. The measured values presented are adjusted means

Outcome measures

Outcome measures
Measure	Placebo Respimat n=34 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=31 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Weekly Mean Nighttime Awakenings Due to Asthma Symptoms	-0.318 units on a scale Standard Error 0.080	-0.257 units on a scale Standard Error 0.078	-0.392 units on a scale Standard Error 0.084

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline in Trough (pre-dose) Forced expiratory volume in 1 second (FEV1) measured at week 12.

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Trough FEV1 Change From Baseline	0.060 Litres Standard Deviation 0.032	0.017 Litres Standard Deviation 0.108	0.085 Litres Standard Deviation 0.163

SECONDARY outcome

Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline of area under the curve (AUC) from 0 to 3 h for FEV1 (FEV1 AUC 0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
FEV1 AUC (0-3h) Change From Baseline	0.104 Litres Standard Deviation 0.043	0.072 Litres Standard Deviation 0.114	0.077 Litres Standard Deviation 0.116

SECONDARY outcome

Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline in maximum forced vital capacity (FVC) measured within the first 3 hours after administration of trial medication (FVC peak (0-3h)) after 12 weeks of treatment.

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
FVC Peak (0-3h) Change From Baseline	0.210 Litres Standard Deviation 0.054	0.136 Litres Standard Deviation 0.143	0.060 Litres Standard Deviation 0.085

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline of trough (pre-dose) forced vital capacity (FVC) measured 10 min before the administration of trial medication after 12 weeks of treatment.

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Trough FVC Change From Baseline	0.155 Litres Standard Deviation 0.060	-0.027 Litres Standard Deviation 0.133	-0.050 Litres Standard Deviation 0.226

SECONDARY outcome

Timeframe: 10 minutes before drug administration and 30 minutes, 1 hour (h), 2h and 3h after drug administration at baseline and week 12

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline of area under the curve (AUC) from 0 to 3 h for FVC (FVC AUC0-3h) after 12 weeks of treatment. The AUC was calculated by using the trapezoidal rule divided by the observation time (3h).

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
FVC AUC (0-3h) Change From Baseline	0.164 Litres Standard Deviation 0.037	0.035 Litres Standard Deviation 0.105	0.003 Litres Standard Deviation 0.130

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline in individual FEV1 measurements at each timepoint after 12 weeks

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Individual FEV1 Measurements Time: 0 hours	0.06 Litres Standard Deviation 0.03	0.02 Litres Standard Deviation 0.11	0.09 Litres Standard Deviation 0.16
Individual FEV1 Measurements Time: 30 minutes	0.11 Litres Standard Deviation 0.09	0.03 Litres Standard Deviation 0.13	0.12 Litres Standard Deviation 0.11
Individual FEV1 Measurements Time: 1 hour	0.11 Litres Standard Deviation 0.08	0.10 Litres Standard Deviation 0.13	0.12 Litres Standard Deviation 0.04
Individual FEV1 Measurements Time: 2 hours	0.12 Litres Standard Deviation 0.05	0.09 Litres Standard Deviation 0.13	0.04 Litres Standard Deviation 0.16
Individual FEV1 Measurements Time: 3 hours	0.10 Litres Standard Deviation 0.05	0.06 Litres Standard Deviation 0.13	0.05 Litres Standard Deviation 0.11

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Population: Full analysis set including only 5 years olds capable of providing technically acceptable pulmonary function tests (PFTs). No imputation for missing data was employed.

Change from baseline in individual FVC measurements at each timepoint after 12 weeks

Outcome measures

Outcome measures
Measure	Placebo Respimat n=4 Participants Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=7 Participants Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=2 Participants Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Individual FVC Measurements Time: 0 hours	0.16 Litres Standard Deviation 0.06	-0.03 Litres Standard Deviation 0.13	-0.05 Litres Standard Deviation 0.23
Individual FVC Measurements Time: 30 minutes	0.13 Litres Standard Deviation 0.07	0.04 Litres Standard Deviation 0.15	0.06 Litres Standard Deviation 0.08
Individual FVC Measurements Time: 1 hour	0.18 Litres Standard Deviation 0.04	0.06 Litres Standard Deviation 0.14	0.05 Litres Standard Deviation 0.10
Individual FVC Measurements Time: 2 hours	0.16 Litres Standard Deviation 0.04	0.02 Litres Standard Deviation 0.10	-0.03 Litres Standard Deviation 0.16
Individual FVC Measurements Time: 3 hours	0.19 Litres Standard Deviation 0.07	0.04 Litres Standard Deviation 0.13	-0.03 Litres Standard Deviation 0.13

Adverse Events

Placebo Respimat

Serious events: 3 serious events

Other events: 24 other events

Deaths: 0 deaths

Tio R2.5

Serious events: 0 serious events

Other events: 19 other events

Deaths: 0 deaths

Tio R5

Serious events: 0 serious events

Other events: 16 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo Respimat n=34 participants at risk Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 participants at risk Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=31 participants at risk Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Infections and infestations Appendicitis	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Bronchopneumonia	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Viral upper respiratory tract infection	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Asthma	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days

Other adverse events

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo Respimat n=34 participants at risk Inhalation of placebo solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R2.5 n=36 participants at risk Inhalation of 2.5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler	Tio R5 n=31 participants at risk Inhalation of 5μg tiotropium bromide solution once daily for 12 weeks, delivered by the Respimat Inhaler.
Gastrointestinal disorders Dry mouth	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Gastrointestinal disorders Mouth ulceration	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Gastrointestinal disorders Vomiting	8.8% 3/34 • From first drug intake until 30 days after last drug intake, up to 119 days	8.3% 3/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
General disorders Pyrexia	17.6% 6/34 • From first drug intake until 30 days after last drug intake, up to 119 days	8.3% 3/36 • From first drug intake until 30 days after last drug intake, up to 119 days	9.7% 3/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Bronchitis	11.8% 4/34 • From first drug intake until 30 days after last drug intake, up to 119 days	2.8% 1/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Ear infection	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	2.8% 1/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Gastroenteritis	0.00% 0/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Nasopharyngitis	14.7% 5/34 • From first drug intake until 30 days after last drug intake, up to 119 days	19.4% 7/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Pharyngitis	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Pneumonia	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	2.8% 1/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Respiratory tract infection viral	11.8% 4/34 • From first drug intake until 30 days after last drug intake, up to 119 days	8.3% 3/36 • From first drug intake until 30 days after last drug intake, up to 119 days	9.7% 3/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Rhinitis	8.8% 3/34 • From first drug intake until 30 days after last drug intake, up to 119 days	5.6% 2/36 • From first drug intake until 30 days after last drug intake, up to 119 days	9.7% 3/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Sinusitis	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	2.8% 1/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Infections and infestations Upper respiratory tract infection	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	8.3% 3/36 • From first drug intake until 30 days after last drug intake, up to 119 days	16.1% 5/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Nervous system disorders Headache	0.00% 0/34 • From first drug intake until 30 days after last drug intake, up to 119 days	5.6% 2/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Reproductive system and breast disorders Balanoposthitis	0.00% 0/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Asthma	26.5% 9/34 • From first drug intake until 30 days after last drug intake, up to 119 days	13.9% 5/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Cough	8.8% 3/34 • From first drug intake until 30 days after last drug intake, up to 119 days	11.1% 4/36 • From first drug intake until 30 days after last drug intake, up to 119 days	6.5% 2/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Nasal congestion	2.9% 1/34 • From first drug intake until 30 days after last drug intake, up to 119 days	8.3% 3/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Rhinitis allergic	0.00% 0/34 • From first drug intake until 30 days after last drug intake, up to 119 days	5.6% 2/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	8.8% 3/34 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/36 • From first drug intake until 30 days after last drug intake, up to 119 days	9.7% 3/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Respiratory, thoracic and mediastinal disorders Wheezing	0.00% 0/34 • From first drug intake until 30 days after last drug intake, up to 119 days	5.6% 2/36 • From first drug intake until 30 days after last drug intake, up to 119 days	0.00% 0/31 • From first drug intake until 30 days after last drug intake, up to 119 days
Skin and subcutaneous tissue disorders Urticaria	5.9% 2/34 • From first drug intake until 30 days after last drug intake, up to 119 days	2.8% 1/36 • From first drug intake until 30 days after last drug intake, up to 119 days	3.2% 1/31 • From first drug intake until 30 days after last drug intake, up to 119 days