Trial Outcomes & Findings for BI 1356 (Linagliptin) in Combination With Metformin and a Sulphonylurea in Type 2 Diabetes (NCT NCT00602472)

Last Updated: 2014-03-28

Results Overview

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 24 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1058 participants

Primary outcome timeframe

Baseline and week 24

Results posted on

2014-03-28

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo Patients randomized to receive treatment with matching placebo	Linagliptin Patients randomized to receive treatment with Linagliptin 5mg
Overall Study STARTED	263	792
Overall Study COMPLETED	242	734
Overall Study NOT COMPLETED	21	58

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Patients randomized to receive treatment with matching placebo	Linagliptin Patients randomized to receive treatment with Linagliptin 5mg
Overall Study Adverse Event	5	23
Overall Study Protocol Violation	4	19
Overall Study Withdrawal by Subject	8	14
Overall Study Other incl. lack of efficacy	4	2

Baseline Characteristics

BI 1356 (Linagliptin) in Combination With Metformin and a Sulphonylurea in Type 2 Diabetes

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=263 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=792 Participants Patients randomized to receive treatment with Linagliptin 5mg	Total n=1055 Participants Total of all reporting groups
Age, Continuous	57.6 Years STANDARD_DEVIATION 9.7 • n=5 Participants	58.3 Years STANDARD_DEVIATION 9.9 • n=7 Participants	58.1 Years STANDARD_DEVIATION 9.8 • n=5 Participants
Sex: Female, Male Female	136 Participants n=5 Participants	421 Participants n=7 Participants	557 Participants n=5 Participants
Sex: Female, Male Male	127 Participants n=5 Participants	371 Participants n=7 Participants	498 Participants n=5 Participants
Body mass index (BMI) continuous	28.16 kg/m^2 STANDARD_DEVIATION 4.52 • n=5 Participants	28.38 kg/m^2 STANDARD_DEVIATION 4.79 • n=7 Participants	28.33 kg/m^2 STANDARD_DEVIATION 4.72 • n=5 Participants
Glycosylated Hemoglobin A1 (HbA1c)	8.14 Percent STANDARD_DEVIATION 0.84 • n=5 Participants	8.15 Percent STANDARD_DEVIATION 0.80 • n=7 Participants	8.14 Percent STANDARD_DEVIATION 0.81 • n=5 Participants
Fasting Plasma Glucose (FPG)	162.6 mg/dL STANDARD_DEVIATION 37.1 • n=5 Participants	159.3 mg/dL STANDARD_DEVIATION 36.5 • n=7 Participants	160.1 mg/dL STANDARD_DEVIATION 36.6 • n=5 Participants

PRIMARY outcome

Timeframe: Baseline and week 24

Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on treatment HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
HbA1c Change From Baseline to Week 24	-0.10 Percent Standard Error 0.05	-0.72 Percent Standard Error 0.03

SECONDARY outcome

Timeframe: Baseline and week 6

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 6 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
HbA1c Change From Baseline to Week 6	-0.18 Percent Standard Error 0.03	-0.67 Percent Standard Error 0.02

SECONDARY outcome

Timeframe: Baseline and week 12

Population: The Full Analysis Set (FAS) included all treated and randomised patients with a baseline and at least one on-treatment. HbA1c measurement available. Last observation carried forward (LOCF) was used as the imputation rule.

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 12 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
HbA1c Change From Baseline to Week 12	-0.15 Percent Standard Error 0.04	-0.84 Percent Standard Error 0.03

SECONDARY outcome

Timeframe: Baseline and week 18

HbA1c is measured as a percentage. Thus, this change from baseline reflects the Week 18 HbA1c percent minus the baseline HbA1c percent. Means are treatment adjusted for baseline HbA1c and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
HbA1c Change From Baseline to Week 18	-0.11 Percent Standard Error 0.05	-0.81 Percent Standard Error 0.03

SECONDARY outcome

Timeframe: Baseline and week 24

Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

This change from baseline reflects the Week 24 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=248 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=739 Participants Patients randomized to receive treatment with Linagliptin 5mg
FPG Change From Baseline to Week 24	8.1 mg/dL Standard Error 2.4	-4.6 mg/dL Standard Error 1.4

SECONDARY outcome

Timeframe: Baseline and week 6

Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

This change from baseline reflects the Week 6 FPG minus the baseline FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=248 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=739 Participants Patients randomized to receive treatment with Linagliptin 5mg
FPG Change From Baseline to Week 6	6.3 mg/dL Standard Error 2.0	-11.5 mg/dL Standard Error 1.2

SECONDARY outcome

Timeframe: Baseline and week 12

Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

This change from baseline reflects the Week 12 FPG minus the baseline FPG. Means are treatment adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication.

Outcome measures

Outcome measures
Measure	Placebo n=248 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=739 Participants Patients randomized to receive treatment with Linagliptin 5mg
FPG Change From Baseline to Week 12	6.2 mg/dL Standard Error 2.0	-9.5 mg/dL Standard Error 1.2

SECONDARY outcome

Timeframe: Baseline and week 18

Population: This population includes the FAS using the LOCF imputation, with the further restriction of patients with a baseline and post-baseline FPG value.

This change from baseline reflects the Week 18 FPG minus the Week 0 FPG. Means are treatment-adjusted for baseline HbA1c, baseline FPG and previous anti-diabetic medication

Outcome measures

Outcome measures
Measure	Placebo n=248 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=739 Participants Patients randomized to receive treatment with Linagliptin 5mg
FPG Change From Baseline to Week 18	7.4 mg/dL Standard Error 2.2	-4.7 mg/dL Standard Error 1.3

SECONDARY outcome

Timeframe: Baseline and week 24

Population: This population includes the FAS with baseline HbA1c \>= 7.0%. Non-completers were considered as failure imputation (NCF).

The percentage of patients with an HbA1c value below 7% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 7%. Only patients with baseline HbA1c \>= 7%

Outcome measures

Outcome measures
Measure	Placebo n=247 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=742 Participants Patients randomized to receive treatment with Linagliptin 5mg
Percentage of Patients With HbA1c <7.0% at Week 24	8.1 percentage of patients 0	29.2 percentage of patients 0

SECONDARY outcome

Timeframe: Baseline and week 24

Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
Percentage of Patients With HbA1c < 7.0% at Week 24	9.2 percentage of patients	31.2 percentage of patients

SECONDARY outcome

Timeframe: Baseline and week 24

Population: This population includes the FAS with baseline HbA1c \>= 6.5%. Non-completers were considered as failure imputation (NCF).

The percentage of patients with an HbA1c value below 6.5% at week 24 was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c above 6.5%. Only patients with baseline HbA1c \>= 6.5%

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=777 Participants Patients randomized to receive treatment with Linagliptin 5mg
Percentage of Patients With HbA1c <6.5% at Week 24	4.2 percentage of patients 0	13.1 percentage of patients 0

SECONDARY outcome

Timeframe: Baseline and week 24

Population: This population includes the Full Analysis Set (FAS). Non-completers were considered as failure imputation (NCF).

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
Percentage of Patients With HbA1c<6.5% at Week 24	4.2 percentage of patients	13.1 percentage of patients

SECONDARY outcome

Timeframe: Baseline and week 24

Population: The Full Analysis Set (FAS) included all patients with a baseline and at least one on treatment HbA1c measurement available. Non-completers were considered as failure imputation (NCF).

The percentage of patients with an HbA1c reduction greater than 0.5% at week 24 from baseline was calculated for each treatment arm. If a patient did not have an HbA1c value at week 24 they were considered a failure, so HbA1c reduction less than 0.5%

Outcome measures

Outcome measures
Measure	Placebo n=262 Participants Patients randomized to receive treatment with matching placebo	Linagliptin n=778 Participants Patients randomized to receive treatment with Linagliptin 5mg
Percentage of Patients Who Have a HbA1c Lowering by 0.5% at Week 24	30.2 percentage of patients 0	58.2 percentage of patients 0

Adverse Events

Placebo

Serious events: 10 serious events

Other events: 94 other events

Deaths: 0 deaths

Linagliptin

Serious events: 25 serious events

Other events: 273 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo n=263 participants at risk Patients randomized to receive treatment with matching placebo	Linagliptin n=792 participants at risk Patients randomized to receive treatment with Linagliptin 5mg
Infections and infestations Nasopharyngitis	4.6% 12/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	5.2% 41/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Upper respiratory tract infection	9.1% 24/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	5.8% 46/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Urinary tract infection	5.3% 14/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	3.2% 25/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Metabolism and nutrition disorders Hyperglycaemia	8.7% 23/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	5.6% 44/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Metabolism and nutrition disorders Hypoglycaemia	14.8% 39/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	22.7% 180/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days

Additional Information

Boehringer Ingelheim Call Center

Boehringer Ingelheim Pharmaceuticals

Phone: 1-800-243-0127

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo n=263 participants at risk Patients randomized to receive treatment with matching placebo	Linagliptin n=792 participants at risk Patients randomized to receive treatment with Linagliptin 5mg
Blood and lymphatic system disorders Bone marrow failure	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Cardiac disorders Angina pectoris	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Cardiac disorders Angina unstable	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Cardiac disorders Myocardial infarction	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Cardiac disorders Myocarditis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Eye disorders Eye swelling	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Eye disorders Glaucoma	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Eye disorders Ocular hyperaemia	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Eye disorders Retinal detachment	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Eye disorders Vitreous haemorrhage	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Constipation	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Gingival swelling	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Lip swelling	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Mouth ulceration	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Nausea	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Gastrointestinal disorders Vomiting	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
General disorders Asthenia	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
General disorders Chest discomfort	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
General disorders Pyrexia	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Hepatobiliary disorders Cholecystitis acute	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Hepatobiliary disorders Cholelithiasis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Bronchitis	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Diverticulitis	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Otitis media chronic	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Pyelonephritis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Respiratory tract infection	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Upper respiratory tract infection	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Urinary tract infection	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Infections and infestations Wound infection	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Contusion	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Fall	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.25% 2/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Femoral neck fracture	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Fibula fracture	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Head injury	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Joint dislocation	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Joint sprain	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Ligament rupture	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Rib fracture	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Road traffic accident	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Injury, poisoning and procedural complications Subdural haematoma	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Metabolism and nutrition disorders Diabetic ketoacidosis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Metabolism and nutrition disorders Hyperglycaemia	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Metabolism and nutrition disorders Hypertriglyceridaemia	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Musculoskeletal and connective tissue disorders Back pain	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.25% 2/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Nervous system disorders Carpal tunnel syndrome	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Nervous system disorders Tension headache	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Renal and urinary disorders Ketonuria	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Renal and urinary disorders Renal impairment	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Renal and urinary disorders Urinary bladder polyp	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.00% 0/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Respiratory, thoracic and mediastinal disorders Nasal oedema	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Skin and subcutaneous tissue disorders Erythema	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Skin and subcutaneous tissue disorders Ingrowing nail	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Vascular disorders Circulatory collapse	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Vascular disorders Hypertension	0.38% 1/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Vascular disorders Hypertensive crisis	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.25% 2/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days
Vascular disorders Hypotension	0.00% 0/263 • From day of first drug dose until 7 days after last dose, with an average of 166 days	0.13% 1/792 • From day of first drug dose until 7 days after last dose, with an average of 166 days