Trial Outcomes & Findings for Dabigatran Etexilate vs Enoxaparin in Prevention of Venous Thromboembolism (VTE) Post Total Knee Replacement (NCT NCT00152971)

Last Updated: 2014-05-05

Results Overview

Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy). All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

2615 participants

Primary outcome timeframe

First administration until 12-15 days

Results posted on

2014-05-05

Participant Flow

The treatment period is from first administration of study medication, until 3 days after last administration of study medication. Treatment duration is planned for 12 - 15 days. The study period is from first administration of study medication until day 84 - 91.

Whilst 2615 patients were enrolled/randomised to treatment post surgery in this trial, only 2596 started treatment. Therefore, 19 patients were randomised but not treated (treatment was planned to start post surgery).

Participant milestones

Participant milestones
Measure	Dabigatran 220mg qd (once daily) oral	Dabigatran 150mg qd (once daily) oral	Enoxaparin 30mg bid (twice daily) subcutaneous
Overall Study STARTED	857	871	868
Overall Study COMPLETED	806	823	819
Overall Study NOT COMPLETED	51	48	49
Treatment STARTED	857	871	868
Treatment COMPLETED	786	808	788
Treatment NOT COMPLETED	71	63	80

Reasons for withdrawal

Reasons for withdrawal
Measure	Dabigatran 220mg qd (once daily) oral	Dabigatran 150mg qd (once daily) oral	Enoxaparin 30mg bid (twice daily) subcutaneous
Overall Study Adverse Event	12	10	9
Overall Study Protocol Violation	10	11	8
Overall Study Lost to Follow-up	17	14	13
Overall Study Withdrawal by Subject	9	8	14
Overall Study Other	3	5	5
Treatment Adverse Event	49	40	54
Treatment Protocol Violation	8	6	10
Treatment Lost to Follow-up	1	2	1
Treatment Withdrawal by Subject	4	4	5
Treatment Other	9	11	10

Baseline Characteristics

Dabigatran Etexilate vs Enoxaparin in Prevention of Venous Thromboembolism (VTE) Post Total Knee Replacement

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Dabigatran 220mg n=857 Participants qd (once daily) oral	Dabigatran 150mg n=871 Participants qd (once daily) oral	Enoxaparin n=868 Participants 30mg bid (twice daily) subcutaneous	Total n=2596 Participants Total of all reporting groups
Age, Continuous	66.2 Years STANDARD_DEVIATION 9.5 • n=5 Participants	65.9 Years STANDARD_DEVIATION 9.5 • n=7 Participants	66.3 Years STANDARD_DEVIATION 9.6 • n=5 Participants	66.1 Years STANDARD_DEVIATION 9.5 • n=4 Participants
Sex: Female, Male Female	486 Participants n=5 Participants	507 Participants n=7 Participants	504 Participants n=5 Participants	1497 Participants n=4 Participants
Sex: Female, Male Male	371 Participants n=5 Participants	364 Participants n=7 Participants	364 Participants n=5 Participants	1099 Participants n=4 Participants
Body Mass Index	31.6 kg/m^2 STANDARD_DEVIATION 6.0 • n=5 Participants	31.4 kg/m^2 STANDARD_DEVIATION 6.1 • n=7 Participants	31.4 kg/m^2 STANDARD_DEVIATION 6.0 • n=5 Participants	31.5 kg/m^2 STANDARD_DEVIATION 6.1 • n=4 Participants

PRIMARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for distal and proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died)

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=604 Participants qd (once daily) oral	Dabigatran 150mg n=649 Participants qd (once daily) oral	Enoxaparin n=643 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period	188 Participants	219 Participants	163 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - major (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis, Pulmonary Embolism, or had died by a Venous Thromboembolic Event-related death)

Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=618 Participants qd (once daily) oral	Dabigatran 150mg n=656 Participants qd (once daily) oral	Enoxaparin n=668 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period	21 Participants	20 Participants	15 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - pDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram for proximal Deep Vein Thrombosis, or had confirmed symptomatic Deep Vein Thrombosis)

Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=614 Participants qd (once daily) oral	Dabigatran 150mg n=656 Participants qd (once daily) oral	Enoxaparin n=664 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period	15 Participants	20 Participants	10 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - tDVT (all patients who had surgery and were randomised, received treatment, had an evaluable venogram, or had confirmed symptomatic Deep Vein Thrombosis)

Total Deep Vein Thrombosis as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=600 Participants qd (once daily) oral	Dabigatran 150mg n=648 Participants qd (once daily) oral	Enoxaparin n=639 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Total Deep Vein Thrombosis During Treatment Period	184 Participants	218 Participants	158 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - op (all patients who are treated and operated)

Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=857 Participants qd (once daily) oral	Dabigatran 150mg n=871 Participants qd (once daily) oral	Enoxaparin n=868 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period	7 Participants	6 Participants	5 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - op

Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=857 Participants qd (once daily) oral	Dabigatran 150mg n=871 Participants qd (once daily) oral	Enoxaparin n=868 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Pulmonary Embolism During Treatment Period	6 Participants	0 Participants	5 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Full Analysis Set - op

All cause death, as adjudicated by the VTE events committee

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=857 Participants qd (once daily) oral	Dabigatran 150mg n=871 Participants qd (once daily) oral	Enoxaparin n=868 Participants 30mg bid (twice daily) subcutaneous
Number of Participants Who Died During Treatment Period	1 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 3 months

Population: Patients with any data available during follow-up

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=840 Participants qd (once daily) oral	Dabigatran 150mg n=861 Participants qd (once daily) oral	Enoxaparin n=853 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period symptotic Deep Vein Thrombosis	2 Participants	4 Participants	2 Participants
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period Pulmonary Embolism	2 Participants	0 Participants	2 Participants
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period death	1 Participants	2 Participants	2 Participants
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period Total VTE and all-cause mortality	7 Participants	7 Participants	10 Participants
Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period asymptotic Deep Vein Thrombosis	2 Participants	1 Participants	4 Participants

SECONDARY outcome

Timeframe: First administration until 12-15 days

Population: Treated set

Major bleeding events were defined as * fatal * clinically overt associated with loss of haemoglobin \>=20g/L in excess of what was expected * clinically overt leading to the transfusion of \>=2 units packed cells or whole blood in excess of what was expected * symptomatic retroperitoneal, intracranial, intraocular or intraspinal * requiring treatment cessation * leading to re-operation Clinically-relevant was defined as * spontaneous skin hematoma greater than or equal to 25 cm² * wound hematoma greater than or equal to 100 cm² * spontaneous nose bleed lasting longer than 5 min * macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention * spontaneous rectal bleeding (more than a spot on toilet paper) * gingival bleeding lasting longer than 5 min * any other bleeding event considered clinically relevant by the investigator Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.

Outcome measures

Outcome measures
Measure	Dabigatran 220mg n=857 Participants qd (once daily) oral	Dabigatran 150mg n=871 Participants qd (once daily) oral	Enoxaparin n=868 Participants 30mg bid (twice daily) subcutaneous
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Major	5 Participants	5 Participants	12 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Clinically relevant	23 Participants	22 Participants	21 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period Minor	46 Participants	45 Participants	51 Participants
Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period None	783 Participants	799 Participants	784 Participants

Adverse Events

Dabigatran 220mg

Serious events: 59 serious events

Other events: 718 other events

Deaths: 0 deaths

Dabigatran 150mg

Serious events: 57 serious events

Other events: 724 other events

Deaths: 0 deaths

Enoxaparin

Serious events: 45 serious events

Other events: 711 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

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	Dabigatran 220mg n=857 participants at risk qd (once daily) oral	Dabigatran 150mg n=871 participants at risk qd (once daily) oral	Enoxaparin n=868 participants at risk 30mg bid (twice daily) subcutaneous
Blood and lymphatic system disorders Anaemia	5.6% 48/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.4% 47/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.3% 46/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Gastrointestinal disorders Constipation	26.7% 229/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	30.8% 268/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	28.2% 245/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Gastrointestinal disorders Dyspepsia	4.8% 41/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	4.5% 39/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.1% 44/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Gastrointestinal disorders Nausea	23.1% 198/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	23.4% 204/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	21.8% 189/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Gastrointestinal disorders Vomiting	12.3% 105/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	12.6% 110/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	10.9% 95/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
General disorders Oedema peripheral	28.5% 244/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	31.6% 275/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	29.3% 254/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
General disorders Pyrexia	18.0% 154/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	18.0% 157/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	19.2% 167/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Injury, poisoning and procedural complications Anaemia postoperative	5.6% 48/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.2% 63/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.4% 64/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Injury, poisoning and procedural complications Post procedural oedema	7.0% 60/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.0% 61/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.0% 52/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Injury, poisoning and procedural complications Post procedural pain	12.8% 110/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	13.1% 114/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	9.7% 84/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Investigations Body temperature increased	5.6% 48/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.7% 58/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.9% 60/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Metabolism and nutrition disorders Hypokalaemia	5.5% 47/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.3% 46/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.4% 47/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Musculoskeletal and connective tissue disorders Arthralgia	4.3% 37/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.2% 54/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.0% 52/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Musculoskeletal and connective tissue disorders Joint swelling	4.7% 40/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	4.0% 35/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.1% 44/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Musculoskeletal and connective tissue disorders Pain in extremity	6.4% 55/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.9% 69/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.7% 67/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Nervous system disorders Dizziness	6.5% 56/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.8% 59/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	9.1% 79/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Nervous system disorders Headache	4.2% 36/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.3% 46/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	4.3% 37/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Psychiatric disorders Insomnia	11.7% 100/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	12.1% 105/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	12.6% 109/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Renal and urinary disorders Urinary retention	8.4% 72/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	9.4% 82/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.9% 60/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Skin and subcutaneous tissue disorders Pruritus	4.4% 38/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	5.1% 44/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	6.0% 52/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.
Vascular disorders Deep vein thrombosis	10.0% 86/857 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	10.7% 93/871 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.	7.5% 65/868 • First administration until (usually) day 21, i.e., treatment period + 3 days. Treatment emergent events (last medication + 3 days); The usual treatment period was 12 to 15 days with up to 18 days. Only one patient was treated for 33 days.