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Clinical Trial Results:
A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery

Summary
EudraCT number	2018-004237-32
Trial protocol	BE HU PL PT BG ES GR LT IT
Global end of trial date	06 Apr 2021

Results information
Results version number	v1(current)
This version publication date	22 Apr 2022
First version publication date	22 Apr 2022
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

70033093THR2001

ISRCTN number

US NCT number

NCT03891524

WHO universal trial number (UTN)

Sponsor organisation name

Janssen Research & Development, LLC

Sponsor organisation address

920 Route 202, South Raritan, United States, 08869

Public contact

Clinical Registry Group, Janssen Research & Development, LLC, clinicaltrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen Research & Development, LLC, clinicaltrialsEU@its.jnj.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

06 Apr 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

06 Apr 2021

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to determine the efficacy of JNJ-70033093 in preventing total venous thromboembolism (VTE) events (proximal and/or distal deep vein thrombosis (DVT) [asymptomatic confirmed by venography assessment or objectively confirmed symptomatic], nonfatal pulmonary embolism (PE), or any death) during the treatment period.

Protection of trial subjects

This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. The safety evaluations included adverse events,including non-serious adverse events, serious adverse events, adverse events of interest (that is, bleeding events, liver enzyme elevations and clinical liver events, and wound or joint complications), clinical laboratory tests (that is, hematology, clinical chemistry, urinalysis), and physical examinations.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Jun 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 47

Country: Number of subjects enrolled

Belgium: 49

Country: Number of subjects enrolled

Bulgaria: 77

Country: Number of subjects enrolled

Brazil: 8

Country: Number of subjects enrolled

Canada: 5

Country: Number of subjects enrolled

Spain: 87

Country: Number of subjects enrolled

Greece: 81

Country: Number of subjects enrolled

Hungary: 107

Country: Number of subjects enrolled

Israel: 59

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Japan: 134

Country: Number of subjects enrolled

Poland: 217

Country: Number of subjects enrolled

Portugal: 79

Country: Number of subjects enrolled

Russian Federation: 20

Country: Number of subjects enrolled

Turkey: 23

Country: Number of subjects enrolled

Ukraine: 84

Country: Number of subjects enrolled

United States: 155

Worldwide total number of subjects

1242

EEA total number of subjects

707

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

409

From 65 to 84 years

817

85 years and over

Subject disposition

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Recruitment details

No text entered

Screening details

A total of 1,242 subjects were randomized and included in the ITT population.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

JNJ-70033093 25 mg Once Daily + Placebo

Arm description

Subjects received JNJ-70033093 25 mg (1*25 milligrams [mg] capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

JNJ-70033093 25 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) once daily.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received 1 placebo capsule orally in the morning and 2 placebo capsules in the evening.

JNJ-70033093 50 mg once daily + Placebo

Arm description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received 2 matching placebo capsules orally.

Investigational medicinal product name

JNJ-70033093 50 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 50 mg (2*25 mg capsules orally in the morning) once daily.

JNJ-70033093 25 mg + Placebo Twice daily (BID)

Arm description

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received 1 matching placebo capsule orally, twice daily.

Investigational medicinal product name

JNJ-70033093 25 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) orally twice daily.

JNJ-70033093 50 mg BID

Arm description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

JNJ-70033093 50 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 50 mg (2*25 mg capsules) BID orally.

JNJ-70033093 200 mg Once Daily + Placebo

Arm description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received 2 matching placebo capsules orally, in the evening.

Investigational medicinal product name

JNJ-70033093 200 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 200 mg (2*100 mg capsules in the morning) orally once daily.

JNJ-70033093 100 mg + Placebo BID

Arm description

Subjects received JNJ-70033093 100 mg (1*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received 1 matching placebo capsule BID orally.

Investigational medicinal product name

JNJ-70033093 100 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 100 mg (1*100 mg capsule) BID orally.

JNJ-70033093 200 mg BID

Arm description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days.

Arm type

Experimental

Investigational medicinal product name

JNJ-70033093 200 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Subjects received JNJ-70033093 200 mg (2*100 mg capsules) BID orally.

Enoxaparin 40 mg Once Daily

Arm description

Subjects received enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Arm type

Active comparator

Investigational medicinal product name

Enoxaparin 40 mg

Investigational medicinal product code

Other name

BMS-986177

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subjects received enoxaparin 40 mg once daily subcutaneously.

Number of subjects in period 1	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Started	34	150	153	150	149	152	153	301
Safety analysis set	33 ^[1]	150	148 ^[2]	148 ^[3]	147	149 ^[4]	148 ^[5]	296 ^[6]
Completed	34	149	151	149	147	150	151	299
Not completed	0	1	2	1	2	2	2	2
Adverse event, serious fatal	-	-	-	-	-	-	-	1
Consent withdrawn by subject	-	1	2	1	2	2	2	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.
[4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.
[5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.
[6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: Among 1242 intent to treat (ITT) subjects,1,219 subjects received at least one dose of study drug and were included in the safety analysis set.

Baseline characteristics

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Reporting group title

JNJ-70033093 25 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 25 mg (1*25 milligrams [mg] capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg once daily + Placebo

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 25 mg + Placebo Twice daily (BID)

Reporting group description

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg BID

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 100 mg + Placebo BID

Reporting group description

Subjects received JNJ-70033093 100 mg (1*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg BID

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

Enoxaparin 40 mg Once Daily

Reporting group description

Subjects received enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Reporting group values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily	Total
Number of subjects	34	150	153	150	149	152	153	301	1242
Age categorical
Units: Subjects
From 50-64 years	9	51	47	43	51	55	49	104	409
65 years and over	25	99	106	107	98	97	104	197	833
Age continuous
Units: years
arithmetic mean (standard deviation)	68.1 ± 5.74	67.9 ± 8.03	68.4 ± 8.49	68.8 ± 8.17	68 ± 8.25	67 ± 8	68.6 ± 7.76	67.8 ± 7.97	-
Sex: Female, Male
Units: subjects
Female	24	107	113	108	108	102	106	208	876
Male	10	43	40	42	41	50	47	93	366

End points

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Reporting group title

JNJ-70033093 25 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 25 mg (1*25 milligrams [mg] capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg once daily + Placebo

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 25 mg + Placebo Twice daily (BID)

Reporting group description

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg BID

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 100 mg + Placebo BID

Reporting group description

Subjects received JNJ-70033093 100 mg (1*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg BID

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

Enoxaparin 40 mg Once Daily

Reporting group description

Subjects received enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Subject analysis set title

Female

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Male

Subject analysis set type

Intention-to-treat

Subject analysis set description

Participants received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Age: Less than or Equal to (<=) 68 years

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Age: Greater than (>) 68 years

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Weight: Less than or Equal to (<=) 82 kilograms (kg)

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Weight: Greater than (>) 82 kg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Creatinine clearance (CRCL): Less than (<) 90

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

CRCL: Greater than or equal to (>=) 90

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 (either 25 mg, 50 mg, 100 mg or 200 mg) once daily or twice daily orally for 10 to 14 postoperative days.

Subject analysis set title

Overall

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects received JNJ-70033093 ( either 25 mg, 50 mg, 100 mg or 200 mg ) once daily or twice daily orally for 10 to 14 postoperative days.

Primary: Number of Subjects with Total Venous Thromboembolism (VTE) (CEC-adjudicated)

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End point title

Number of Subjects with Total Venous Thromboembolism (VTE) (CEC-adjudicated) ^[1]

End point description

Total VTE was defined as the composite of clinical events committee (CEC)-adjudicated proximal and/or distal Deep Vein Thrombosis (DVT) (asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic), nonfatal pulmonary embolism (PE), or any death. The modified Intent-to-treat (mITT) analysis set included all intent-to-treat (ITT) subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic proximal DVT, PE or death as adjudicated by the CEC.

End point type

Primary

End point timeframe

Up to Day 14

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Descriptive statistics was done, no inferential statistical analysis was performed.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	127	129	124	123	134	131	252
Units: subjects	7	30	27	14	8	12	10	54

No statistical analyses for this end point

Secondary: Number of Subjects with any Bleeding Event (CEC-adjudicated)

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End point title

Number of Subjects with any Bleeding Event (CEC-adjudicated)

End point description

Any bleeding was defined as the composite of major bleeding according to the International Society on Thrombosis and Haemostasis (ISTH) criteria modified for the surgical setting, clinically relevant nonmajor bleeding events, or minimal bleeding events as assessed by the CEC. The safety analysis set was a subset of the intent to treat (ITT) analysis set, consisting of all ITT subjects who received at least 1 dose (partial or complete) of study drug.

End point type

Secondary

End point timeframe

Up to Day 14; Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	8	2	7	11	7	6	12
Up to Day 52	0	8	2	7	11	7	6	12

No statistical analyses for this end point

Secondary: Number of Subjects with Total VTE (CEC-adjudicated) Up to Day 52

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End point title

Number of Subjects with Total VTE (CEC-adjudicated) Up to Day 52

End point description

Total VTE was defined as the composite of CEC-adjudicated proximal and/or DVT (asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic), nonfatal PE, or any death. The mITT analysis set included all the subjects in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Here,‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	253
Units: subjects	7	30	27	14	8	12	10	54

No statistical analyses for this end point

Secondary: Number of Subjects With Composite of Major and Clinically Relevant Non-Major CRNM Bleeding Events (CEC-adjudicated)

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End point title

Number of Subjects With Composite of Major and Clinically Relevant Non-Major CRNM Bleeding Events (CEC-adjudicated)

End point description

Composite of Major BE: Fatal bleeding; bleeding that is symptomatic and occurs in critical area/organ and/or; extrasurgical site bleeding causing fall in Hb level of 20 g/L or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; surgical site bleeding that requires second intervention open,arthroscopic,endovascular,or hemarthrosis resulting in prolonged hospitalization, deep wound infection and/or either unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. CRNM bleeding: acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE is still considered clinically relevant for example: Epistaxis, Gastrointestinal bleed,Hematuria,Bruising/ecchymosis,Hemoptysis,Hematoma.The analysis set: safety set. Here,‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14, Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	2	0	2	1	1	1	5
Up to Day 52	0	2	0	2	2	1	1	5

No statistical analyses for this end point

Secondary: Number of Subjects with Major Bleeding Events (CEC-adjudicated)

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End point title

Number of Subjects with Major Bleeding Events (CEC-adjudicated)

End point description

Number of subjects with major bleeding events (adjudicated by CEC) were reported. Major bleeding was defined as: Fatal bleeding; Bleeding that is symptomatic and occurs in critical area/organ and/or; Extrasurgical site bleeding causing fall in hemoglobin (Hb) level of 20 grams per liter (g/L) or more, or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding, and/or; Surgical site bleeding that requires second intervention open, arthroscopic, endovascular, or hemarthrosis resulting in prolonged hospitalization or a deep wound infection and/or; Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability. The safety analysis set was a subset of the ITT analysis set, consisting of all ITT subjects who received at least 1 dose (partial or complete) of study drug.

End point type

Secondary

End point timeframe

Up to Day 14; Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	0	0	0	0	0	0	1
Up to Day 52	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with CRNM Bleeding Events (CEC-adjudicated)

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End point title

Number of Subjects with CRNM Bleeding Events (CEC-adjudicated)

End point description

Number of subjects with CRNM bleeding events (adjudicated by CEC) were reported. CRNM bleeding events were defined as acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE and meets and is still considered clinically relevant for example: Epistaxis, Gastrointestinal bleed, Hematuria, Bruising/ecchymosis, Hemoptysis, Hematoma. The safety analysis set was a subset of the ITT analysis set, consisting of all ITT subjects who received at least 1 dose (partial or complete) of study drug.

End point type

Secondary

End point timeframe

Up to Day 14; Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	2	0	2	1	1	1	4
Up to Day 52	0	2	0	2	2	1	1	4

No statistical analyses for this end point

Secondary: Number of Subjects with Minimal Bleeding Events (CEC-adjudicated)

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End point title

Number of Subjects with Minimal Bleeding Events (CEC-adjudicated)

End point description

Number of participants with minimal bleeding events (adjudicated by CEC) were reported. Minimal bleeding event was defined as any bleeding event not met major or CRNM criteria. The safety analysis set was a subset of the ITT analysis set, consisting of all ITT subjects who received at least 1 dose (partial or complete) of study drug.

End point type

Secondary

End point timeframe

Up to Day 14; Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	6	2	5	8	7	4	8
Up to Day 52	0	6	2	5	9	7	5	8

No statistical analyses for this end point

Secondary: Number of Subjects with Major or CRNM Bleeding Events (CEC-adjudicated)

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End point title

Number of Subjects with Major or CRNM Bleeding Events (CEC-adjudicated)

End point description

Major Bleeding:Fatal bleeding; That is symptomatic and occurs in critical area/organ and/or;Extrasurgical site bleeding causing fall in Hb level of 20 g/L or more,or leading to transfusion of 2 or more units of whole blood or red cells with temporal association within 24-48 hours to bleeding,and/or;Surgical site bleeding that requires second intervention open,arthroscopic,endovascular,or hemarthrosis resulting in prolonged hospitalization or deep wound infection and/or;Surgical site bleeding that is unexpected and prolonged and/or sufficiently large to cause hemodynamic instability.CRNM bleeding:acute clinically overt bleeding that does not satisfy additional criteria required for bleeding event to be defined as major BE,still considered clinically relevant for example: Epistaxis, Gastrointestinal bleed,Hematuria,Bruising/ecchymosis,Hemoptysis,Hematoma.The safety analysis set was used.

End point type

Secondary

End point timeframe

Up to Day 14; Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	33	150	148	148	147	149	148	296
Units: subjects
Up to Day 14	0	2	0	2	1	1	1	5
Up to Day 52	0	0	0	0	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Major VTE (CEC-adjudicated)

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End point title

Number of Subjects with Major VTE (CEC-adjudicated)

End point description

Number of subjects with major VTE (adjudicated by CEC) were reported. Major VTE was defined as a composite of proximal DVT (asymptomatic confirmed by venography or objectively confirmed symptomatic), nonfatal PE, or any death. mITT at Day 14 included all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	127	129	124	123	134	131	252
Units: subjects	0	2	1	1	0	2	0	4

No statistical analyses for this end point

Secondary: Number of Subjects with Major VTE (CEC-adjudicated) Up to Day 52

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End point title

Number of Subjects with Major VTE (CEC-adjudicated) Up to Day 52

End point description

Number of subjects with major VTE (adjudicated by CEC) were reported. Major VTE was defined as a composite of proximal DVT (asymptomatic confirmed by venography or objectively confirmed symptomatic), nonfatal PE, or any death. The mITT analysis set included all the subjects in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	253
Units: subjects	0	2	1	1	0	2	0	4

No statistical analyses for this end point

Secondary: Number of Subjects with Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)

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End point title

Number of Subjects with Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)

End point description

Number of subjects with proximal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. The mITT analysis set at Day 14 includes all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). The subjects whose venography result is not evaluable distal but no proximal clot.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	29	134	133	128	128	136	135	259
Units: subjects
Asymptomatic	0	0	0	0	0	0	0	1
Symptomatic	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Proximal DVT (CEC-adjudicated) Up to Day 52

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End point title

Number of Participants with Proximal DVT (CEC-adjudicated) Up to Day 52

End point description

Number of subjects with proximal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. The mITT analysis set at Week 6 included all the subjects in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Also included the subjects whose venography result was not evaluable distal but no proximal clot.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	29	135	133	128	128	137	135	260
Units: subjects
Asymptomatic	0	0	0	0	0	0	0	1
Symptomatic	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated)

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End point title

Number of Subjects with Distal DVT (CEC-adjudicated)

End point description

Number of subjects with distal DVT (CEC-adjudicated) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. The mITT analysis set at Day 14 included all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here, ‘N’ (number of subjects analyzed) signifies those participants who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	252
Units: subjects
Asymptomatic	7	27	26	13	8	10	10	50
Symptomatic	0	2	0	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated) Up to Day 52

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End point title

Number of Subjects with Distal DVT (CEC-adjudicated) Up to Day 52

End point description

Number of subjects with distal DVT (adjudicated by CEC) were reported. DVT asymptomatic confirmed by venography assessment of the operated leg or objectively confirmed symptomatic. mITT included all the subjects in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	253
Units: subjects
Asymptomatic (Up to Day 52)	7	27	26	13	8	10	10	50
Symptomatic (Up to Day 52)	0	2	2	0	0	1	0	0

No statistical analyses for this end point

Secondary: Number of Subjects with Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)

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End point title

Number of Subjects with Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)

End point description

Number of subjects with nonfatal PE (adjudicated by CEC) were reported. mITT at Day 14 included all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	127	129	124	123	134	131	252
Units: subjects	0	0	0	1	0	1	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with Nonfatal PE (CEC-adjudicated) Up to Day 52

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End point title

Number of Subjects with Nonfatal PE (CEC-adjudicated) Up to Day 52

End point description

Number of subjects with nonfatal PE (adjudicated by CEC) were reported. The mITT analysis set included all the participants in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	253
Units: subjects	0	0	0	1	0	1	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with Deaths (CEC-adjudicated)

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End point title

Number of Subjects with Deaths (CEC-adjudicated)

End point description

Number of subjects with deaths (CEC-adjudicated) were reported. mITT at Day 14 included all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	127	129	124	123	134	131	252
Units: subjects	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Number of Subjects with Deaths (CEC-adjudicated) Up to Day 52

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End point title

Number of Subjects with Deaths (CEC-adjudicated) Up to Day 52

End point description

Number of subjects with deaths (CEC-adjudicated) were reported. mITT at Week 6 included all the subjects in mITT at Day 14 plus the subjects who had symptomatic/asymptomatic VTE events (DVT, non-fatal PE or any death) after day 17 through day 52. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 52

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Number of subjects analysed	28	128	129	124	123	135	131	253
Units: subjects	0	0	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (V/F) of JNJ-70033093

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End point title

Apparent Volume of Distribution (V/F) of JNJ-70033093

End point description

V/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint. This endpoint was planned to be analyzed for overall subjects and not group wise.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Overall
Number of subjects analysed	921
Units: Liter
geometric mean (geometric coefficient of variation)	148 ± 77.6

No statistical analyses for this end point

Secondary: Apparent Clearance (CL/F) of JNJ-70033093

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End point title

Apparent Clearance (CL/F) of JNJ-70033093

End point description

Apparent clearance of a drug was defined as a measure of the rate at which a drug got metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure. This outcome measure was planned to be analyzed for overall subjects and not group wise.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Overall
Number of subjects analysed	921
Units: Liter per hour (L/h)
geometric mean (geometric coefficient of variation)	8.33 ± 45.8

No statistical analyses for this end point

Secondary: Impact of Selected Demographics: Sex on CL/F

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End point title

Impact of Selected Demographics: Sex on CL/F

End point description

Impact of sex on CL/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Arms are created based on sex (male and female) to report the effect of sex on CL/F. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Female	Male
Number of subjects analysed	653	268
Units: Litres per hour (L/h)
geometric mean (geometric coefficient of variation)	7.70 ± 48.4	9.87 ± 36.3

No statistical analyses for this end point

Secondary: Impact of Selected Demographic: Age on CL/F

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End point title

Impact of Selected Demographic: Age on CL/F

End point description

Impact of age CL/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint. Arms are created based on age to report the effect of age on CL/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Age: Less than or Equal to (<=) 68 years	Age: Greater than (>) 68 years
Number of subjects analysed	464	457
Units: L/h
geometric mean (geometric coefficient of variation)	9.33 ± 45.5	7.32 ± 41.1

No statistical analyses for this end point

Secondary: Impact of Selected Demographic: Weight on CL/F

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End point title

Impact of Selected Demographic: Weight on CL/F

End point description

Impact of weight) on CL/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoints. Arms are created based on weight to report the effect of weight on CL/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Weight: Less than or Equal to (<=) 82 kilograms (kg)	Weight: Greater than (>) 82 kg
Number of subjects analysed	486	435
Units: L/h
geometric mean (geometric coefficient of variation)	7.56 ± 41.2	9.20 ± 46.9

No statistical analyses for this end point

Secondary: Impact of Selected Laboratory Values: Renal Function on CL/F

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End point title

Impact of Selected Laboratory Values: Renal Function on CL/F

End point description

Impact of renal function on V/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. The outcome measure was reported based on CRCL. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure. Arms are created based on CRCL to report the effect of renal function on CL/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Creatinine clearance (CRCL): Less than (<) 90	CRCL: Greater than or equal to (>=) 90
Number of subjects analysed	442	447
Units: L/h
geometric mean (geometric coefficient of variation)	7.21 ± 43.4	9.40 ± 43.7

No statistical analyses for this end point

Secondary: Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex

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End point title

Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex

End point description

Impact of sex on V/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure. Arms are created based on sex (male and female) to report the effect of sex on V/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Female	Male
Number of subjects analysed	653	268
Units: Liters
geometric mean (geometric coefficient of variation)	140 ± 81.2	166 ± 69.0

No statistical analyses for this end point

Secondary: Impact of Selected Demographics : Age on V/F

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End point title

Impact of Selected Demographics : Age on V/F

End point description

Impact of age on V/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this outcome measure. Arms are created based on age to report the effect of sex on V/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Age: Less than or Equal to (<=) 68 years	Age: Greater than (>) 68 years
Number of subjects analysed	464	457
Units: Liters
geometric mean (geometric coefficient of variation)	160 ± 83.2	135 ± 66.9

No statistical analyses for this end point

Secondary: Impact of Selected Demographics : Weight on V/F

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End point title

Impact of Selected Demographics : Weight on V/F

End point description

Impact of weight on V/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint. Arms are created based on weight to report the effect of weight on CV/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Weight: Less than or Equal to (<=) 82 kilograms (kg)	Weight: Greater than (>) 82 kg
Number of subjects analysed	486	435
Units: Liters
geometric mean (geometric coefficient of variation)	127 ± 65.4	171 ± 80.9

No statistical analyses for this end point

Secondary: Impact of Selected Laboratory Values: Renal Function on V/F

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End point title

Impact of Selected Laboratory Values: Renal Function on V/F

End point description

Impact of renal function on V/F was assessed. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. The outcome measure was reported based on CRCL. Here, ‘N’ (number of subjects analyzed) signifies those subjects who were evaluable for this endpoint. Arms are created based on CRCL to report the effect of renal function on V/F.

End point type

Secondary

End point timeframe

Up to Day 14

End point values	Creatinine clearance (CRCL): Less than (<) 90	CRCL: Greater than or equal to (>=) 90
Number of subjects analysed	442	447
Units: Liters
geometric mean (geometric coefficient of variation)	136 ± 66.3	160 ± 84.5

No statistical analyses for this end point

Secondary: Relationship between JNJ-70033093 Dose Levels with Total VTE

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End point title

Relationship between JNJ-70033093 Dose Levels with Total VTE ^[2]

End point description

Relationship between JNJ-70033093 dose levels with total VTE was determined using a multiple comparison procedures and modeling (MCP-Mod) approach. The mITT analysis set at Day 14 included all ITT participants who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here 'number' signifies the estimated response rate.

End point type

Secondary

End point timeframe

Up to 14 days

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint was planned to be analyzed for specified arms only.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID
Number of subjects analysed	33	150	148	148	147	149	148
Units: percentage of subjects
number (confidence interval 95%)	0.35 (0.17 to 0.52)	0.21 (0.16 to 0.25)	0.20 (0.15 to 0.24)	0.13 (0.10 to 0.16)	0.09 (0.07 to 0.12)	0.09 (0.06 to 0.11)	0.07 (0.03 to 0.10)

No statistical analyses for this end point

Secondary: Relationship Between JNJ-70033093 Dose Levels with Composite of Major or Clinically Relevant Nonmajor Bleeding Events

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End point title

Relationship Between JNJ-70033093 Dose Levels with Composite of Major or Clinically Relevant Nonmajor Bleeding Events ^[3]

End point description

Relationship between JNJ-70033093 dose levels with composite of major or clinically relevant nonmajor bleeding events was determined using a MCP-Mod approach. The mITT analysis set at Day 14 included all ITT subjects who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here 'number' signifies the estimated response rate.

End point type

Secondary

End point timeframe

Up to 14 days

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint was planned to be analyzed for specified arms only.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID
Number of subjects analysed	33	150	148	148	147	149	148
Units: percentage of subjects
number (confidence interval 95%)	0.02 (0.00 to 0.17)	0.01 (0.00 to 0.03)	0.01 (0.00 to 0.04)	0.01 (0.00 to 0.02)	0.01 (0.00 to 0.02)	0.01 (0.00 to 0.02)	0.01 (0.00 to 0.02)

No statistical analyses for this end point

Secondary: Relationship between JNJ-70033093 Dose Levels with Major Bleeding Events

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End point title

Relationship between JNJ-70033093 Dose Levels with Major Bleeding Events ^[4]

End point description

Relationship between JNJ-70033093 dose levels with major bleeding events was determined using a MCP-Mod approach. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here "99999" indicates that data was not available as there were no major bleeding events.

End point type

Secondary

End point timeframe

Up to 14 days

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint was planned to be analyzed for specified arms only.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID
Number of subjects analysed	33	150	148	148	147	149	148
Units: unitless
geometric mean (geometric coefficient of variation)	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999	99999 ± 99999

No statistical analyses for this end point

Secondary: Relationship between JNJ-70033093 Dose Levels with Clinically Relevant Nonmajor Bleeding Events

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End point title

Relationship between JNJ-70033093 Dose Levels with Clinically Relevant Nonmajor Bleeding Events ^[5]

End point description

Relationship between JNJ-70033093 dose levels with clinically relevant nonmajor bleeding events was determined using a MCP-Mod approach. The mITT analysis set at Day 14 included all ITT participants who received at least 1 dose of study drug with an evaluable venography assessment or a confirmed symptomatic VTE event (DVT, non-fatal PE or any death). Here '99999' indicates that data was not available as there were no clinically relevant nonmajor events.

End point type

Secondary

End point timeframe

Up to 14 days

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint was planned to be analyzed for specified arms only.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID
Number of subjects analysed	33	150	148	148	147	149	148
Units: unitless
geometric mean (geometric coefficient of variation)	99999 ± 99999	0.0133 ± 863.1	99999 ± 99999	0.0136 ± 854.4	0.00680 ± 1212.4	0.00671 ± 1220.7	0.00676 ± 0.00676

No statistical analyses for this end point

Secondary: Relationship between JNJ-70033093 Dose Levels with Minimal Bleeding Events

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End point title

Relationship between JNJ-70033093 Dose Levels with Minimal Bleeding Events ^[6]

End point description

Relationship between JNJ-70033093 dose levels with minimal bleeding events was determined using a MCP-Mod approach. The PK analysis set consisted of subjects who received at least 1 dose of milvexian and had at least one valid blood sample drawn for PK analysis. Here "99999" indicates that data was not available as there were no minimal bleeding events.

End point type

Secondary

End point timeframe

Up to 14 days

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint was planned to be analyzed for specified arms only.

End point values	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID
Number of subjects analysed	33	150	150	148	147	149	148
Units: unitless
geometric mean (geometric coefficient of variation)	99999 ± 99999	0.0533 ± 422.7	0.0135 ± 857.3	0.0476 ± 448.7	0.0612 ± 392.9	0.0470 ± 451.9	0.0338 ± 536.6

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to 6 weeks

Adverse event reporting additional description

The safety analysis set is a subset of the intent to treat (ITT) analysis set, consisting of all ITT participants who received at least 1 dose (partial or complete) of study drug.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

JNJ-70033093 25 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 25 mg (1*25 mg capsule) once daily and 1 placebo capsule in the morning and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg once daily + Placebo

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 25 mg + Placebo Twice daily (BID)

Reporting group description

Subjects received JNJ-70033093 25 milligram (mg) (1*25 mg capsule) and 1 placebo capsule twice daily (BID), orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 50 mg BID

Reporting group description

Subjects received JNJ-70033093 50 mg (2*25 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg Once Daily + Placebo

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules in the morning) once daily and 2 placebo capsules in the evening, orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 100 mg + Placebo BID

Reporting group description

Subjects received JNJ-70033093 100 mg (1*100 mg capsule) and 1 placebo capsule BID orally for 10 to 14 postoperative days.

Reporting group title

JNJ-70033093 200 mg BID

Reporting group description

Subjects received JNJ-70033093 200 mg (2*100 mg capsules) BID orally for 10 to 14 postoperative days.

Reporting group title

Enoxaparin 40 mg Once Daily

Reporting group description

Subjects received enoxaparin 40 mg once daily subcutaneously for 10 to 14 postoperative days.

Serious adverse events	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 33 (3.03%)	2 / 150 (1.33%)	5 / 148 (3.38%)	5 / 148 (3.38%)	2 / 147 (1.36%)	5 / 149 (3.36%)	2 / 148 (1.35%)	11 / 296 (3.72%)
number of deaths (all causes)	0	0	0	0	0	0	0	1
number of deaths resulting from adverse events
Investigations
Cardiovascular Evaluation
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	1 / 147 (0.68%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Full Blood Count Decreased
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	1 / 149 (0.67%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoglobin Decreased
subjects affected / exposed	0 / 33 (0.00%)	1 / 150 (0.67%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Craniocerebral Injury
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
Periprosthetic Fracture
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural Haemorrhage
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep Vein Thrombosis
subjects affected / exposed	1 / 33 (3.03%)	1 / 150 (0.67%)	1 / 148 (0.68%)	1 / 148 (0.68%)	0 / 147 (0.00%)	2 / 149 (1.34%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 1	0 / 1	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral Artery Embolism
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial Fibrillation
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	1 / 148 (0.68%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Ischaemic Stroke
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	1 / 148 (0.68%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	1 / 148 (0.68%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	1 / 147 (0.68%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	1 / 148 (0.68%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	1 / 148 (0.68%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary Embolism
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	1 / 149 (0.67%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory Failure
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	1 / 148 (0.68%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Compartment Syndrome
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	1 / 148 (0.68%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Covid-19
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device Related Infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	1 / 149 (0.67%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	1 / 148 (0.68%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	0 / 296 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wound Infection
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Hyponatraemia
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Electrolyte Imbalance
subjects affected / exposed	0 / 33 (0.00%)	0 / 150 (0.00%)	0 / 148 (0.00%)	0 / 148 (0.00%)	0 / 147 (0.00%)	0 / 149 (0.00%)	0 / 148 (0.00%)	1 / 296 (0.34%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	JNJ-70033093 25 mg Once Daily + Placebo	JNJ-70033093 50 mg once daily + Placebo	JNJ-70033093 25 mg + Placebo Twice daily (BID)	JNJ-70033093 50 mg BID	JNJ-70033093 200 mg Once Daily + Placebo	JNJ-70033093 100 mg + Placebo BID	JNJ-70033093 200 mg BID	Enoxaparin 40 mg Once Daily
Total subjects affected by non serious adverse events
subjects affected / exposed	0 / 33 (0.00%)	6 / 150 (4.00%)	9 / 148 (6.08%)	8 / 148 (5.41%)	3 / 147 (2.04%)	4 / 149 (2.68%)	3 / 148 (2.03%)	17 / 296 (5.74%)
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 33 (0.00%)	6 / 150 (4.00%)	9 / 148 (6.08%)	8 / 148 (5.41%)	3 / 147 (2.04%)	4 / 149 (2.68%)	3 / 148 (2.03%)	17 / 296 (5.74%)
occurrences all number	0	6	9	8	3	4	3	17

More information

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Were there any global substantial amendments to the protocol? Yes

10 Sep 2019

The overall reasons for the amendment was to modify the study design with regards to the planned and optional doses and to remove the option for preoperative dosing and some minor editorial changes.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

No notable study limitations were identified by the sponsor.

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Clinical trials

Clinical Trial Results: A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Subjects with Total Venous Thromboembolism (VTE) (CEC-adjudicated)

Primary: Number of Subjects with Total Venous Thromboembolism (VTE) (CEC-adjudicated)

Secondary: Number of Subjects with any Bleeding Event (CEC-adjudicated)

Secondary: Number of Subjects with any Bleeding Event (CEC-adjudicated)

Secondary: Number of Subjects with Total VTE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Total VTE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects With Composite of Major and Clinically Relevant Non-Major CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects With Composite of Major and Clinically Relevant Non-Major CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Major Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Major Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Minimal Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Minimal Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Major or CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Major or CRNM Bleeding Events (CEC-adjudicated)

Secondary: Number of Subjects with Major VTE (CEC-adjudicated)

Secondary: Number of Subjects with Major VTE (CEC-adjudicated)

Secondary: Number of Subjects with Major VTE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Major VTE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)

Secondary: Number of Subjects with Proximal Deep Vein Thrombosis (DVT) (CEC-adjudicated)

Secondary: Number of Participants with Proximal DVT (CEC-adjudicated) Up to Day 52

Secondary: Number of Participants with Proximal DVT (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated)

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated)

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Distal DVT (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)

Secondary: Number of Subjects with Nonfatal Pulmonary Embolism (PE) (CEC-adjudicated)

Secondary: Number of Subjects with Nonfatal PE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Nonfatal PE (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Deaths (CEC-adjudicated)

Secondary: Number of Subjects with Deaths (CEC-adjudicated)

Secondary: Number of Subjects with Deaths (CEC-adjudicated) Up to Day 52

Secondary: Number of Subjects with Deaths (CEC-adjudicated) Up to Day 52

Secondary: Apparent Volume of Distribution (V/F) of JNJ-70033093

Secondary: Apparent Volume of Distribution (V/F) of JNJ-70033093

Secondary: Apparent Clearance (CL/F) of JNJ-70033093

Secondary: Apparent Clearance (CL/F) of JNJ-70033093

Secondary: Impact of Selected Demographics: Sex on CL/F

Secondary: Impact of Selected Demographics: Sex on CL/F

Secondary: Impact of Selected Demographic: Age on CL/F

Secondary: Impact of Selected Demographic: Age on CL/F

Secondary: Impact of Selected Demographic: Weight on CL/F

Secondary: Impact of Selected Demographic: Weight on CL/F

Secondary: Impact of Selected Laboratory Values: Renal Function on CL/F

Secondary: Impact of Selected Laboratory Values: Renal Function on CL/F

Secondary: Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex

Secondary: Impact of Selected Demographics: Apparent Clearance (CL/F) Based on Sex

Secondary: Impact of Selected Demographics : Age on V/F

Secondary: Impact of Selected Demographics : Age on V/F

Secondary: Impact of Selected Demographics : Weight on V/F

Secondary: Impact of Selected Demographics : Weight on V/F

Secondary: Impact of Selected Laboratory Values: Renal Function on V/F

Secondary: Impact of Selected Laboratory Values: Renal Function on V/F

Secondary: Relationship between JNJ-70033093 Dose Levels with Total VTE

Secondary: Relationship between JNJ-70033093 Dose Levels with Total VTE

Secondary: Relationship Between JNJ-70033093 Dose Levels with Composite of Major or Clinically Relevant Nonmajor Bleeding Events

Secondary: Relationship Between JNJ-70033093 Dose Levels with Composite of Major or Clinically Relevant Nonmajor Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Major Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Major Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Clinically Relevant Nonmajor Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Clinically Relevant Nonmajor Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Minimal Bleeding Events

Secondary: Relationship between JNJ-70033093 Dose Levels with Minimal Bleeding Events

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Randomized, Open-Label, Study Drug-Dose Blind, Multicenter Study to Evaluate the Efficacy and Safety of JNJ-70033093 (BMS-986177), an Oral Factor XIa Inhibitor, Versus Subcutaneous Enoxaparin in Subjects Undergoing Elective Total Knee Replacement Surgery