Trial Outcomes & Findings for BI 425809 in Patients With Cognitive Impairment Due to Alzheimer's Disease. (NCT NCT02788513)

Last Updated: 2020-11-06

Results Overview

The ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, orientation and praxis with a total score range of 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. Multiple comparison procedures and modelling (MCPmod) in combination with mixed model repeated measures (MMRM) is used for primary analysis of the primary endpoint. MMRM included fixed, categorical covariates of treatment, visit, baseline Mini Mental State Examination MMSE (\>=20, \<20) and treatment-by-visit interaction, as well as the continuous fixed covariates of baseline and baseline-by-visit interaction. Patient was considered as random effect. The unstructured covariance structure was used to model the within patient measurements. The same MMRM model used in the primary analysis is used for the secondary analysis of the primary endpoint.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

611 participants

Primary outcome timeframe

On day 1 (visit 2, baseline) and day 85 (end of trial)

Results posted on

2020-11-06

Participant Flow

This is a multi-centre, double-blind, parallel-group, randomised controlled study to investigate efficacy and safety of orally administered BI 425809 during a 12-week treatment period compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.

Subjects were screened prior to participation and attended a specialist site which ensured that they strictly met all inclusion/exclusion criteria. Subjects were not to be allocated to a treatment group if any of the criteria were violated. One subject was randomized by error via Interactive Response Technology (IRT) but never took a drug.

Participant milestones

Participant milestones
Measure	2 mg BI 425809 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Overall Study STARTED	123	122	122	123	120
Overall Study COMPLETED	114	114	114	117	115
Overall Study NOT COMPLETED	9	8	8	6	5

Reasons for withdrawal

Reasons for withdrawal
Measure	2 mg BI 425809 Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Overall Study Withdrawal by Subject	3	0	2	3	1
Overall Study Lost to Follow-up	1	0	0	0	1
Overall Study Adverse Event	5	8	4	2	2
Overall Study Protocol Violation	0	0	1	1	0
Overall Study Subject decided to stop taking treatment	0	0	1	0	0
Overall Study Decision by the study team	0	0	0	0	1

Baseline Characteristics

Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	2 mg BI 425809 n=123 Participants Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=122 Participants Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=122 Participants Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=123 Participants Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=120 Participants Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Total n=610 Participants Total of all reporting groups
Age, Continuous	72.3 Years STANDARD_DEVIATION 7.5 • n=123 Participants	72.5 Years STANDARD_DEVIATION 8.2 • n=122 Participants	74.4 Years STANDARD_DEVIATION 6.9 • n=122 Participants	72.9 Years STANDARD_DEVIATION 7.7 • n=123 Participants	72.4 Years STANDARD_DEVIATION 7.9 • n=120 Participants	72.9 Years STANDARD_DEVIATION 7.7 • n=610 Participants
Sex: Female, Male Female	68 Participants n=123 Participants	62 Participants n=122 Participants	66 Participants n=122 Participants	64 Participants n=123 Participants	64 Participants n=120 Participants	324 Participants n=610 Participants
Sex: Female, Male Male	55 Participants n=123 Participants	60 Participants n=122 Participants	56 Participants n=122 Participants	59 Participants n=123 Participants	56 Participants n=120 Participants	286 Participants n=610 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	17 Participants n=123 Participants	22 Participants n=122 Participants	11 Participants n=122 Participants	16 Participants n=123 Participants	20 Participants n=120 Participants	86 Participants n=610 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	101 Participants n=123 Participants	98 Participants n=122 Participants	106 Participants n=122 Participants	103 Participants n=123 Participants	94 Participants n=120 Participants	502 Participants n=610 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	5 Participants n=123 Participants	2 Participants n=122 Participants	5 Participants n=122 Participants	4 Participants n=123 Participants	6 Participants n=120 Participants	22 Participants n=610 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=123 Participants	0 Participants n=122 Participants	0 Participants n=122 Participants	0 Participants n=123 Participants	0 Participants n=120 Participants	0 Participants n=610 Participants
Race (NIH/OMB) Asian	11 Participants n=123 Participants	10 Participants n=122 Participants	12 Participants n=122 Participants	14 Participants n=123 Participants	11 Participants n=120 Participants	58 Participants n=610 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=123 Participants	2 Participants n=122 Participants	1 Participants n=122 Participants	1 Participants n=123 Participants	2 Participants n=120 Participants	6 Participants n=610 Participants
Race (NIH/OMB) Black or African American	10 Participants n=123 Participants	5 Participants n=122 Participants	4 Participants n=122 Participants	3 Participants n=123 Participants	8 Participants n=120 Participants	30 Participants n=610 Participants
Race (NIH/OMB) White	97 Participants n=123 Participants	103 Participants n=122 Participants	100 Participants n=122 Participants	102 Participants n=123 Participants	93 Participants n=120 Participants	495 Participants n=610 Participants
Race (NIH/OMB) More than one race	0 Participants n=123 Participants	0 Participants n=122 Participants	0 Participants n=122 Participants	0 Participants n=123 Participants	0 Participants n=120 Participants	0 Participants n=610 Participants
Race (NIH/OMB) Unknown or Not Reported	5 Participants n=123 Participants	2 Participants n=122 Participants	5 Participants n=122 Participants	3 Participants n=123 Participants	6 Participants n=120 Participants	21 Participants n=610 Participants
ADASCOG baseline cognitive assessment data	18.8 score on a scale STANDARD_DEVIATION 7.9 • n=123 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.	18.8 score on a scale STANDARD_DEVIATION 7.4 • n=122 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.	19.6 score on a scale STANDARD_DEVIATION 7.8 • n=122 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.	19.6 score on a scale STANDARD_DEVIATION 7.3 • n=123 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.	18.2 score on a scale STANDARD_DEVIATION 8.0 • n=119 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.	19.0 score on a scale STANDARD_DEVIATION 7.7 • n=609 Participants • Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation. The TS was used for safety analyses. One placebo subject was without baseline measures due to study was put on hold.

PRIMARY outcome

Timeframe: On day 1 (visit 2, baseline) and day 85 (end of trial)

Population: Full analysis set (FAS): all randomised patients who were treated with at least one dose of trial medication and had a baseline and at least one corresponding post-baseline on-treatment efficacy assessment for any efficacy endpoint. FAS was used for efficacy analyses.

Outcome measures

Outcome measures
Measure	2 mg BI 425809 n=121 Participants Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=120 Participants Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=121 Participants Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=119 Participants Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=118 Participants Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Change From Baseline in Alzheimer's Disease Assessment Scale-Cognitive Subscale 11 Item (ADAS-Cog11) Total Score After 12 Weeks of Treatment	0.026 score on a scale Standard Deviation 4.864	0.175 score on a scale Standard Deviation 4.471	0.699 score on a scale Standard Deviation 4.313	-0.174 score on a scale Standard Deviation 4.044	0.138 score on a scale Standard Deviation 4.939

SECONDARY outcome

Timeframe: On day 1 (visit 2, baseline) and day 85 (end of trial)

Change from baseline in the ADCS-ADL score after 12 weeks of treatment is presented. The ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. In the full version of the scale, 23 items are rated by the investigator using information supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum score could range from 0 to 78, with higher scores indicating less severe impairment. A positive change indicates an improvement from baseline. Abbreviation: MMSE = Mini Mental State Examination

Outcome measures

Outcome measures
Measure	2 mg BI 425809 n=113 Participants Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=111 Participants Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=110 Participants Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=116 Participants Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=111 Participants Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Change From Baseline in the Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Score After 12 Weeks of Treatment	0.283 score on a scale Standard Deviation 6.805	0.577 score on a scale Standard Deviation 5.852	-1.145 score on a scale Standard Deviation 4.764	-1.828 score on a scale Standard Deviation 7.034	0.261 score on a scale Standard Deviation 4.842

SECONDARY outcome

Timeframe: On day 1 (visit 2, baseline) and day 85 (end of trial)

Clinician's Interview-Based Impression of Change (CIBIC+) score is based on semi-structured interview covering domains of function and cognition. It additionally requires the assessment of psychiatric signs and symptoms. The patient and their caregiver are interviewed and questioned by the clinician. Change rate is based on an unanchored 7-point scale (with 0 being not assessed, 1-3 being very much improved to minimally improved, 4 being no change, and 5-7 being minimally worse to very much worse). For the ANCOVA model, the baseline value for CIBIC+ is represented by CIBIS which is clinician's interview-based impression of severity score (scores range from 0-7, with 0 being not assessed, 1 being normal, and 7 being most extremely ill) in order to adjust for potential baseline heterogeneity. Abbreviation: MMSE = Mini Mental State Examination

Outcome measures

Outcome measures
Measure	2 mg BI 425809 n=114 Participants Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=112 Participants Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=110 Participants Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=116 Participants Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=112 Participants Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Clinician's Interview-Based Impression of Change (CIBIC+) Score After 12 Weeks of Treatment	4.000 score on a scale Standard Deviation 0.941	4.080 score on a scale Standard Deviation 0.773	4.209 score on a scale Standard Deviation 0.679	4.224 score on a scale Standard Deviation 0.781	4.080 score on a scale Standard Deviation 0.829

Adverse Events

2 mg BI 425809

Serious events: 5 serious events

Other events: 17 other events

Deaths: 0 deaths

5 mg BI 425809

Serious events: 4 serious events

Other events: 22 other events

Deaths: 0 deaths

10 mg BI 425809

Serious events: 4 serious events

Other events: 14 other events

Deaths: 0 deaths

25 mg BI 425809

Serious events: 4 serious events

Other events: 19 other events

Deaths: 0 deaths

Placebo Group

Serious events: 5 serious events

Other events: 12 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	2 mg BI 425809 n=123 participants at risk Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=122 participants at risk Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=122 participants at risk Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=123 participants at risk Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=120 participants at risk Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Eye disorders Cataract	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Eye disorders Glaucoma	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Gastrointestinal disorders Pancreatitis acute	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Cardiac disorders Atrial flutter	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Hepatobiliary disorders Cholecystitis acute	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Hepatobiliary disorders Drug-induced liver injury	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Bronchitis	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Gingivitis	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Pneumonia	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Sepsis	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Urinary tract infection bacterial	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Injury, poisoning and procedural complications Fall	1.6% 2/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Injury, poisoning and procedural complications Head injury	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Injury, poisoning and procedural complications Skin laceration	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Metabolism and nutrition disorders Dehydration	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Metabolism and nutrition disorders Hypoglycaemia	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Musculoskeletal and connective tissue disorders Torticollis	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Pancreatic neoplasm	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Nervous system disorders Dementia	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Nervous system disorders Syncope	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Nervous system disorders Transient ischaemic attack	0.81% 1/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Psychiatric disorders Depression	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.00% 0/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.83% 1/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.

Other adverse events

Other adverse events
Measure	2 mg BI 425809 n=123 participants at risk Participants in dose group 1 were orally administered 2 tablets of 1 milligrams (mg) of BI 425809 (Total: 2 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	5 mg BI 425809 n=122 participants at risk Participants in dose group 2 were orally administered 1 tablet of 5 mg of BI 425809 together with 1 tablet of 1 mg / 5 mg and 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	10 mg BI 425809 n=122 participants at risk Participants in dose group 3 were orally administered 2 tablets of 5 mg of BI 425809 (Total: 10 mg) together with 1 tablet of 25 mg placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	25 mg BI 425809 n=123 participants at risk Participants in dose group 4 were orally administered 1 tablet of 25 mg of BI 425809 together with 2 tablets of 1 mg / 5 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.	Placebo Group n=120 participants at risk Participants in the placebo group were orally administered 2 tablets of 1 mg / 5 mg and 1 tablet of 25 mg of placebo match once daily (qd) during 12 weeks. The tablets were to be taken with water in the morning at approximately the same time every day with or without food.
Gastrointestinal disorders Nausea	4.9% 6/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	0.82% 1/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	1.6% 2/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	6.5% 8/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	1.7% 2/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Infections and infestations Nasopharyngitis	2.4% 3/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	5.7% 7/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	2.5% 3/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	2.4% 3/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	2.5% 3/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Nervous system disorders Dizziness	3.3% 4/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	7.4% 9/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	2.5% 3/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	4.9% 6/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	1.7% 2/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.
Nervous system disorders Headache	4.9% 6/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	8.2% 10/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	5.7% 7/122 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	4.1% 5/123 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.	4.2% 5/120 • From first dose of study drug until end of treatment + 28 days of follow-up, up to 16 weeks. Treated set (TS): the TS included all patients treated with at least one dose of trial medication. Patients in the treated set were analysed based on the actual treatment received at the randomisation.

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