Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

A Multi-centre, Randomised, Double-blinded, Controlled, Dose-escalation Trial on Safety and Efficacy of Activated Recombinant FVII Analogue (NN1731) in the Treatment of Joint Bleeds in Congenital Haemophilia Patients With Inhibitors

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00486278

Enrollment

Registered

2007-06-14

Start date

2007-06-30

Completion date

2010-06-30

Last updated

2017-03-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Congenital Bleeding Disorder, Haemophilia A, Haemophilia B

Brief summary

This trial is conducted in Africa, Asia, Europe, Japan, and North and South America. The aim of this trial is to evaluate the safety and efficacy of activated recombinant human factor VII analogue (vatreptocog alfa (activated)) in haemophilia patients with inhibitors.

Interventions

DRUGeptacog alfa (activated)

90 mcg/kg, injected i.v.

DRUGvatreptacog alfa (activated)

5 mcg/kg, injected i.v.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

DOUBLE (Subject, Investigator)

Eligibility

Sex/Gender

MALE

Age

12 Years to No maximum

Healthy volunteers

Inclusion criteria

* 12 years of age or older (at least 18 years in Croatia, France and United Kingdom (UK)) * Clinical diagnosis of congenital haemophilia A or B with a current positive inhibitor titre and a known peak inhibitor of above 5 Bethesda units (BU) (present or in the past) to human FVIII or IX and known antihuman FVIII or IX anamnestic response * Minimum of 2 joint bleeds (haemarthroses of ankles, knees, or elbows) requiring haemostatic drug treatment within the previous 6 months, or at least 4 joint bleeds (hemarthroses of ankles, knees, or elbows) requiring haemostatic drug treatment within the previous 12 months at trial entry

Exclusion criteria

* Known allergy to rFVIIa, and/or suspected allergy to trial product * Platelet count lower than 50,000 mm\^3 based on medical records at trial entry (visit 1) * Any clinical signs or history of thromboembolic events * Advanced atherosclerotic disease * Severe liver disease based on medical records within the past 12 months at trial entry (Visit 1), as defined by alanine aminotransferase (ALAT) above 3 times the upper limit of normal reference range * Known active pseudo tumours (documented bleeding requiring treatment within the last 3 months * Subject had any (major) surgical procedure in the 30 days prior to screening into the trial. a. Catheter, ports and dental extractions do not count as surgeries and will not exclude the subject

Design outcomes

Primary

Measure	Time frame	Description
Number of Adverse Events (AEs)	Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product.	Adverse event is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

Secondary

Measure	Time frame	Description
Haematology: White Cell Count	screening visit, pre-dose and 12 hours after dosing	—
Activated Recombinant Human Factor VII Analogue Activity in the Blood	0-24 hours after trial product administration	—
Prothrombin Time (PT)	pre-dose - 12 hours after trial product administration	The test measures the clotting time of plasma following the activation of tissue factor (TF also called thromboplastin) and calcium to hypocalcemic plasma. PT was provided in percent based on the measured PT in seconds and related/converted with the relevant standard curve. The percent value was derived based on the hyperbolic relation between PT (sec) and % PT activity.
F1 + 2 (Prothrombin Fragments 1+2)	pre-dose - 12 hours after trial product administration	Thrombin and F1+2 are formed in equimolar quantities by the enzymatic cleavage of prothrombin (FII), and F1+2 thus indicate that thrombin has been generated.
Haematology: Platelet Count	screening visit, pre-dose and 12 hours after dosing	—
Activated Partial Thromboplastin Time (aPTT)	pre-dose - 12 hours after trial product administration	The aPTT time measured in clinical samples reflects both the effect of the drugs (generation of thrombin and FXa) and the presence of rFVIIa /rFVIIa analogue in the plasma samples causing a dose dependent shortening of the clotting time.
Cessation of Bleeding: Number of Doses Needed to Control Bleeding	Within 9 hours after first trial product administration or need of additional haemostatic medication within 9 hours after first trial administration additional haemostatic agents required to control bleed (treatment failure)	—
Number of Subjects With Need for Additional Haemostatic Agents	within 24 hours after successful control of bleeding episode with trial product	—
Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )	0-24 hours after trial product administration	—
Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)	0-24 hours after trial product administration	—
Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)	0-24 hours after trial product administration	—
Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)	0-24 hours after trial product administration	—
Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)	0-24 hours after trial product administration	—
Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)	0-24 hours after trial product administration	—
Immunogenicity (Inhibitor Development)	Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product.	Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or rFVIIa.
Biochemistry: ALAT (Alanine Aminotransferase)	screening visit, pre-dose and 12 hours after dosing	—
Biochemistry: Creatinine	screening visit, pre-dose and 12 hours after dosing	—
Haematology: Haemoglobin	screening visit, pre-dose and 12 hours after dosing	—
Haematology: Red Cell Count	screening visit, pre-dose and 12 hours after dosing	—
Haematology: Packed Cell Volume	screening visit, pre-dose and 12 hours after dosing	—

Countries

Argentina, Brazil, Canada, Croatia, France, Hungary, Israel, Italy, Japan, Malaysia, Poland, South Africa, Spain, Taiwan, Thailand, Turkey (Türkiye), United Kingdom, United States

Participant flow

Recruitment details

A total of 40 sites were initiated globally in 18 countries, including Argentina, Brazil, Canada, Croatia, France, Hungary, Israel, Italy, Japan, Malaysia, Poland, South Africa, Spain, Turkey, Taiwan, Thailand, the United Kingdom and the United States

Pre-assignment details

A subject could be included in more than one dose escalation cohort with up to one bleeding per cohort, randomised by 4:1 to receive either vatreptacog alfa or rFVIIa 90 (mcg/kg) in a blinded manner.

Participants by arm

Arm	Count
All Subjects A total of 51 subjects with 96 qualifying bleeds were treated in the study. A subject could contribute with up to one qualifying bleeding episode per study arm.	51
Total	51

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Adverse Event	5
Overall Study	Physician Decision	2
Overall Study	Withdrawal by Subject	2

Baseline characteristics

Characteristic	All Subjects
Age, Continuous	28 years STANDARD_DEVIATION 12.4
Sex: Female, Male Female	0 Participants
Sex: Female, Male Male	51 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	6 / 16	3 / 19	3 / 16	1 / 16	0 / 10	8 / 19
serious Total, serious adverse events	2 / 16	3 / 19	2 / 16	2 / 16	0 / 10	2 / 19

Outcome results

Primary

Number of Adverse Events (AEs)

Adverse event is defined as any untoward medical occurrence in a patient or clinical investigation patient administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

Time frame: Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product.

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.

Arm	Measure	Group	Value (NUMBER)
Vatreptacog Alfa 5 mcg/kg	Number of Adverse Events (AEs)	All AEs	10 events
Vatreptacog Alfa 5 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	3 events
Vatreptacog Alfa 10 mcg/kg	Number of Adverse Events (AEs)	All AEs	8 events
Vatreptacog Alfa 10 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	5 events
Vatreptacog Alfa 20 mcg/kg	Number of Adverse Events (AEs)	All AEs	5 events
Vatreptacog Alfa 20 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	2 events
Vatreptacog Alfa 40 mcg/kg	Number of Adverse Events (AEs)	All AEs	5 events
Vatreptacog Alfa 40 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	2 events
Vatreptacog Alfa 80 mcg/kg	Number of Adverse Events (AEs)	All AEs	0 events
Vatreptacog Alfa 80 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	0 events
rFVIIa 90 mcg/kg	Number of Adverse Events (AEs)	All AEs	11 events
rFVIIa 90 mcg/kg	Number of Adverse Events (AEs)	Serious AEs	3 events

Secondary

Activated Partial Thromboplastin Time (aPTT)

The aPTT time measured in clinical samples reflects both the effect of the drugs (generation of thrombin and FXa) and the presence of rFVIIa /rFVIIa analogue in the plasma samples causing a dose dependent shortening of the clotting time.

Time frame: pre-dose - 12 hours after trial product administration

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	102.1 Sec	Standard Deviation 19.4
Vatreptacog Alfa 5 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	120.6 Sec	Standard Deviation 22.6
Vatreptacog Alfa 5 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	111.7 Sec	Standard Deviation 22.4
Vatreptacog Alfa 10 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	79.7 Sec	Standard Deviation 13.9
Vatreptacog Alfa 10 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	126.0 Sec	Standard Deviation 26.4
Vatreptacog Alfa 10 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	107.9 Sec	Standard Deviation 27.7
Vatreptacog Alfa 20 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	68.7 Sec	Standard Deviation 15.7
Vatreptacog Alfa 20 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	122.8 Sec	Standard Deviation 15.9
Vatreptacog Alfa 20 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	107.9 Sec	Standard Deviation 14.8
Vatreptacog Alfa 40 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	52.8 Sec	Standard Deviation 14.1
Vatreptacog Alfa 40 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	119.2 Sec	Standard Deviation 31.3
Vatreptacog Alfa 40 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	104.4 Sec	Standard Deviation 31.2
Vatreptacog Alfa 80 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	48.6 Sec	Standard Deviation 24
Vatreptacog Alfa 80 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	117.4 Sec	Standard Deviation 17.9
Vatreptacog Alfa 80 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	99.3 Sec	Standard Deviation 19.6
rFVIIa 90 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	Pre-dose	113.8 Sec	Standard Deviation 17.4
rFVIIa 90 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	12 hours post-dose	98.6 Sec	Standard Deviation 20.8
rFVIIa 90 mcg/kg	Activated Partial Thromboplastin Time (aPTT)	1 hours post-dose	70.0 Sec	Standard Deviation 9.8

Secondary

Activated Recombinant Human Factor VII Analogue Activity in the Blood

Time frame: 0-24 hours after trial product administration

Population: All randomised patients in top three dosing tiers 3, 4 and 5 who had pharmacokinetic assessments and completed the trial without violation of the protocol in a manner that was judged to affect the pharmacokinetic endpoints were included in the pharmacokinetic analysis set.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 20 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	Pre-dose	0.1 IU/mL	Standard Deviation 0.1
Vatreptacog Alfa 20 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	1 hours post-dose	5.3 IU/mL	Standard Deviation 1.3
Vatreptacog Alfa 20 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	12 hours post-dose	0.4 IU/mL	Standard Deviation 0.4
Vatreptacog Alfa 20 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	24 hours post-dose	0 IU/mL	Standard Deviation 0
Vatreptacog Alfa 40 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	1 hours post-dose	12.8 IU/mL	Standard Deviation 5.3
Vatreptacog Alfa 40 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	12 hours post-dose	2.3 IU/mL	Standard Deviation 4.5
Vatreptacog Alfa 40 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	24 hours post-dose	0 IU/mL	Standard Deviation 0
Vatreptacog Alfa 40 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	Pre-dose	0.1 IU/mL	Standard Deviation 0
Vatreptacog Alfa 80 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	12 hours post-dose	0.3 IU/mL	Standard Deviation 0.3
Vatreptacog Alfa 80 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	1 hours post-dose	19.7 IU/mL	Standard Deviation 7.2
Vatreptacog Alfa 80 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	24 hours post-dose	0 IU/mL	Standard Deviation 0
Vatreptacog Alfa 80 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	Pre-dose	0 IU/mL	Standard Deviation 0
rFVIIa 90 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	24 hours post-dose	0.1 IU/mL	Standard Deviation 0
rFVIIa 90 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	1 hours post-dose	28.0 IU/mL	Standard Deviation 12.6
rFVIIa 90 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	Pre-dose	0.1 IU/mL	Standard Deviation 0
rFVIIa 90 mcg/kg	Activated Recombinant Human Factor VII Analogue Activity in the Blood	12 hours post-dose	14.1 IU/mL	Standard Deviation 27.3

Secondary

Biochemistry: ALAT (Alanine Aminotransferase)

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	22.7 U/L	Standard Deviation 19.9
Vatreptacog Alfa 5 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	26.0 U/L	Standard Deviation 18.7
Vatreptacog Alfa 5 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	20.1 U/L	Standard Deviation 16.8
Vatreptacog Alfa 10 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	29.9 U/L	Standard Deviation 23
Vatreptacog Alfa 10 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	32.8 U/L	Standard Deviation 31.3
Vatreptacog Alfa 10 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	25.6 U/L	Standard Deviation 19.2
Vatreptacog Alfa 20 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	32.4 U/L	Standard Deviation 37.1
Vatreptacog Alfa 20 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	30.6 U/L	Standard Deviation 27.1
Vatreptacog Alfa 20 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	21.4 U/L	Standard Deviation 15.4
Vatreptacog Alfa 40 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	29.1 U/L	Standard Deviation 16.4
Vatreptacog Alfa 40 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	39.3 U/L	Standard Deviation 33.3
Vatreptacog Alfa 40 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	30.9 U/L	Standard Deviation 18.2
Vatreptacog Alfa 80 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	28.1 U/L	Standard Deviation 16.6
Vatreptacog Alfa 80 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	24.2 U/L	Standard Deviation 17.9
Vatreptacog Alfa 80 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	24.5 U/L	Standard Deviation 14.4
rFVIIa 90 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Screening	30.1 U/L	Standard Deviation 21.4
rFVIIa 90 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	12 hours post-dose	45.1 U/L	Standard Deviation 66
rFVIIa 90 mcg/kg	Biochemistry: ALAT (Alanine Aminotransferase)	Pre-dose	49.4 U/L	Standard Deviation 73.7

Secondary

Biochemistry: Creatinine

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Biochemistry: Creatinine	Pre-dose	68.2 micromol/L	Standard Deviation 23.3
Vatreptacog Alfa 5 mcg/kg	Biochemistry: Creatinine	Screening	66.9 micromol/L	Standard Deviation 23.6
Vatreptacog Alfa 5 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	58.3 micromol/L	Standard Deviation 23.6
Vatreptacog Alfa 10 mcg/kg	Biochemistry: Creatinine	Pre-dose	70.1 micromol/L	Standard Deviation 10
Vatreptacog Alfa 10 mcg/kg	Biochemistry: Creatinine	Screening	67.2 micromol/L	Standard Deviation 13.8
Vatreptacog Alfa 10 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	63.1 micromol/L	Standard Deviation 17.7
Vatreptacog Alfa 20 mcg/kg	Biochemistry: Creatinine	Pre-dose	69.8 micromol/L	Standard Deviation 15.3
Vatreptacog Alfa 20 mcg/kg	Biochemistry: Creatinine	Screening	63.6 micromol/L	Standard Deviation 23.3
Vatreptacog Alfa 20 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	70.6 micromol/L	Standard Deviation 16.8
Vatreptacog Alfa 40 mcg/kg	Biochemistry: Creatinine	Pre-dose	69.1 micromol/L	Standard Deviation 19.1
Vatreptacog Alfa 40 mcg/kg	Biochemistry: Creatinine	Screening	67.7 micromol/L	Standard Deviation 15.7
Vatreptacog Alfa 40 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	71.9 micromol/L	Standard Deviation 15.2
Vatreptacog Alfa 80 mcg/kg	Biochemistry: Creatinine	Pre-dose	67.7 micromol/L	Standard Deviation 10.8
Vatreptacog Alfa 80 mcg/kg	Biochemistry: Creatinine	Screening	60.0 micromol/L	Standard Deviation 17.3
Vatreptacog Alfa 80 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	68.0 micromol/L	Standard Deviation 10.7
rFVIIa 90 mcg/kg	Biochemistry: Creatinine	Screening	66.9 micromol/L	Standard Deviation 16
rFVIIa 90 mcg/kg	Biochemistry: Creatinine	12 hours post-dose	70.6 micromol/L	Standard Deviation 14.8
rFVIIa 90 mcg/kg	Biochemistry: Creatinine	Pre-dose	71.1 micromol/L	Standard Deviation 15.2

Secondary

Cessation of Bleeding: Number of Doses Needed to Control Bleeding

Time frame: Within 9 hours after first trial product administration or need of additional haemostatic medication within 9 hours after first trial administration additional haemostatic agents required to control bleed (treatment failure)

Population: All randomised patients for whom at least one of the efficacy variables is assessed were to be included in the full analysis set (FAS). For the outcome measure 1 subject did not contribute to the data.

Arm	Measure	Group	Value (NUMBER)
Vatreptacog Alfa 5 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	3 bleeding episodes
Vatreptacog Alfa 5 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	5 bleeding episodes
Vatreptacog Alfa 5 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	4 bleeding episodes
Vatreptacog Alfa 5 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	3 bleeding episodes
Vatreptacog Alfa 10 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	4 bleeding episodes
Vatreptacog Alfa 10 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	9 bleeding episodes
Vatreptacog Alfa 10 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	3 bleeding episodes
Vatreptacog Alfa 10 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	3 bleeding episodes
Vatreptacog Alfa 20 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	0 bleeding episodes
Vatreptacog Alfa 20 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	7 bleeding episodes
Vatreptacog Alfa 20 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	7 bleeding episodes
Vatreptacog Alfa 20 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	2 bleeding episodes
Vatreptacog Alfa 40 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	5 bleeding episodes
Vatreptacog Alfa 40 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	1 bleeding episodes
Vatreptacog Alfa 40 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	6 bleeding episodes
Vatreptacog Alfa 40 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	4 bleeding episodes
Vatreptacog Alfa 80 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	2 bleeding episodes
Vatreptacog Alfa 80 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	0 bleeding episodes
Vatreptacog Alfa 80 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	4 bleeding episodes
Vatreptacog Alfa 80 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	4 bleeding episodes
rFVIIa 90 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	2 doses	4 bleeding episodes
rFVIIa 90 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	3 doses	7 bleeding episodes
rFVIIa 90 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	treatment failure	2 bleeding episodes
rFVIIa 90 mcg/kg	Cessation of Bleeding: Number of Doses Needed to Control Bleeding	1 dose	6 bleeding episodes

Secondary

F1 + 2 (Prothrombin Fragments 1+2)

Thrombin and F1+2 are formed in equimolar quantities by the enzymatic cleavage of prothrombin (FII), and F1+2 thus indicate that thrombin has been generated.

Time frame: pre-dose - 12 hours after trial product administration

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	443.7 pmol/L	Standard Deviation 414.7
Vatreptacog Alfa 5 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	289.8 pmol/L	Standard Deviation 310.9
Vatreptacog Alfa 5 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	325.9 pmol/L	Standard Deviation 299.4
Vatreptacog Alfa 10 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	241.7 pmol/L	Standard Deviation 162
Vatreptacog Alfa 10 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	131.8 pmol/L	Standard Deviation 48.7
Vatreptacog Alfa 10 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	198.9 pmol/L	Standard Deviation 250.9
Vatreptacog Alfa 20 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	401.6 pmol/L	Standard Deviation 292.6
Vatreptacog Alfa 20 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	139.1 pmol/L	Standard Deviation 50.4
Vatreptacog Alfa 20 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	158.6 pmol/L	Standard Deviation 54.5
Vatreptacog Alfa 40 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	365.9 pmol/L	Standard Deviation 145.4
Vatreptacog Alfa 40 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	121.2 pmol/L	Standard Deviation 34.5
Vatreptacog Alfa 40 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	199.8 pmol/L	Standard Deviation 91.5
Vatreptacog Alfa 80 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	385.7 pmol/L	Standard Deviation 88.8
Vatreptacog Alfa 80 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	125.4 pmol/L	Standard Deviation 45.9
Vatreptacog Alfa 80 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	136.9 pmol/L	Standard Deviation 43.8
rFVIIa 90 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	Pre-dose	169.3 pmol/L	Standard Deviation 56.9
rFVIIa 90 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	12 hour post-dose	268.2 pmol/L	Standard Deviation 158
rFVIIa 90 mcg/kg	F1 + 2 (Prothrombin Fragments 1+2)	1 hour post-dose	309.7 pmol/L	Standard Deviation 284.5

Secondary

Haematology: Haemoglobin

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Haematology: Haemoglobin	Pre-dose	13.8 g/dL	Standard Deviation 2.3
Vatreptacog Alfa 5 mcg/kg	Haematology: Haemoglobin	Screening	13.9 g/dL	Standard Deviation 1.8
Vatreptacog Alfa 5 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	13.5 g/dL	Standard Deviation 2.2
Vatreptacog Alfa 10 mcg/kg	Haematology: Haemoglobin	Pre-dose	14.6 g/dL	Standard Deviation 1.7
Vatreptacog Alfa 10 mcg/kg	Haematology: Haemoglobin	Screening	14.7 g/dL	Standard Deviation 1.6
Vatreptacog Alfa 10 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	13.9 g/dL	Standard Deviation 1.7
Vatreptacog Alfa 20 mcg/kg	Haematology: Haemoglobin	Pre-dose	14.4 g/dL	Standard Deviation 1.2
Vatreptacog Alfa 20 mcg/kg	Haematology: Haemoglobin	Screening	14.2 g/dL	Standard Deviation 1.4
Vatreptacog Alfa 20 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	13.7 g/dL	Standard Deviation 1.2
Vatreptacog Alfa 40 mcg/kg	Haematology: Haemoglobin	Pre-dose	13.9 g/dL	Standard Deviation 2.1
Vatreptacog Alfa 40 mcg/kg	Haematology: Haemoglobin	Screening	14.2 g/dL	Standard Deviation 1.8
Vatreptacog Alfa 40 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	13.0 g/dL	Standard Deviation 2.2
Vatreptacog Alfa 80 mcg/kg	Haematology: Haemoglobin	Pre-dose	14.8 g/dL	Standard Deviation 1.3
Vatreptacog Alfa 80 mcg/kg	Haematology: Haemoglobin	Screening	14.6 g/dL	Standard Deviation 1.3
Vatreptacog Alfa 80 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	14.2 g/dL	Standard Deviation 0.8
rFVIIa 90 mcg/kg	Haematology: Haemoglobin	Screening	13.8 g/dL	Standard Deviation 1.3
rFVIIa 90 mcg/kg	Haematology: Haemoglobin	12 hours post-dose	13.5 g/dL	Standard Deviation 1.3
rFVIIa 90 mcg/kg	Haematology: Haemoglobin	Pre-dose	14.1 g/dL	Standard Deviation 1.3

Secondary

Haematology: Packed Cell Volume

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	41.3 percentage (%)	Standard Deviation 6.1
Vatreptacog Alfa 5 mcg/kg	Haematology: Packed Cell Volume	Screening	41.6 percentage (%)	Standard Deviation 5.1
Vatreptacog Alfa 5 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	40.6 percentage (%)	Standard Deviation 6
Vatreptacog Alfa 10 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	43.1 percentage (%)	Standard Deviation 4
Vatreptacog Alfa 10 mcg/kg	Haematology: Packed Cell Volume	Screening	43.7 percentage (%)	Standard Deviation 3.9
Vatreptacog Alfa 10 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	40.9 percentage (%)	Standard Deviation 4
Vatreptacog Alfa 20 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	42.6 percentage (%)	Standard Deviation 3.2
Vatreptacog Alfa 20 mcg/kg	Haematology: Packed Cell Volume	Screening	42.2 percentage (%)	Standard Deviation 3.6
Vatreptacog Alfa 20 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	40.6 percentage (%)	Standard Deviation 2.9
Vatreptacog Alfa 40 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	42.5 percentage (%)	Standard Deviation 6.3
Vatreptacog Alfa 40 mcg/kg	Haematology: Packed Cell Volume	Screening	42.4 percentage (%)	Standard Deviation 4.3
Vatreptacog Alfa 40 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	39.9 percentage (%)	Standard Deviation 6.8
Vatreptacog Alfa 80 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	44.6 percentage (%)	Standard Deviation 4.6
Vatreptacog Alfa 80 mcg/kg	Haematology: Packed Cell Volume	Screening	44.0 percentage (%)	Standard Deviation 3.3
Vatreptacog Alfa 80 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	42.2 percentage (%)	Standard Deviation 2.9
rFVIIa 90 mcg/kg	Haematology: Packed Cell Volume	Screening	41.6 percentage (%)	Standard Deviation 3.8
rFVIIa 90 mcg/kg	Haematology: Packed Cell Volume	12 hours post-dose	40.4 percentage (%)	Standard Deviation 3.8
rFVIIa 90 mcg/kg	Haematology: Packed Cell Volume	Pre-dose	42.3 percentage (%)	Standard Deviation 3.5

Secondary

Haematology: Platelet Count

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Haematology: Platelet Count	Pre-dose	253.5 10^9 cells/L	Standard Deviation 90.5
Vatreptacog Alfa 5 mcg/kg	Haematology: Platelet Count	12 hours post-dose	242.7 10^9 cells/L	Standard Deviation 83.7
Vatreptacog Alfa 5 mcg/kg	Haematology: Platelet Count	Screening	259.8 10^9 cells/L	Standard Deviation 96.2
Vatreptacog Alfa 10 mcg/kg	Haematology: Platelet Count	Pre-dose	248.6 10^9 cells/L	Standard Deviation 65.2
Vatreptacog Alfa 10 mcg/kg	Haematology: Platelet Count	Screening	253.8 10^9 cells/L	Standard Deviation 82.9
Vatreptacog Alfa 10 mcg/kg	Haematology: Platelet Count	12 hours post-dose	244.8 10^9 cells/L	Standard Deviation 57.4
Vatreptacog Alfa 20 mcg/kg	Haematology: Platelet Count	Pre-dose	252.7 10^9 cells/L	Standard Deviation 50.8
Vatreptacog Alfa 20 mcg/kg	Haematology: Platelet Count	Screening	250.8 10^9 cells/L	Standard Deviation 61.2
Vatreptacog Alfa 20 mcg/kg	Haematology: Platelet Count	12 hours post-dose	255.8 10^9 cells/L	Standard Deviation 61.9
Vatreptacog Alfa 40 mcg/kg	Haematology: Platelet Count	12 hours post-dose	287.0 10^9 cells/L	Standard Deviation 94.8
Vatreptacog Alfa 40 mcg/kg	Haematology: Platelet Count	Screening	276.1 10^9 cells/L	Standard Deviation 75.5
Vatreptacog Alfa 40 mcg/kg	Haematology: Platelet Count	Pre-dose	278.8 10^9 cells/L	Standard Deviation 78
Vatreptacog Alfa 80 mcg/kg	Haematology: Platelet Count	Pre-dose	278.1 10^9 cells/L	Standard Deviation 59
Vatreptacog Alfa 80 mcg/kg	Haematology: Platelet Count	Screening	272.5 10^9 cells/L	Standard Deviation 73.2
Vatreptacog Alfa 80 mcg/kg	Haematology: Platelet Count	12 hours post-dose	266.8 10^9 cells/L	Standard Deviation 53.1
rFVIIa 90 mcg/kg	Haematology: Platelet Count	Pre-dose	271.1 10^9 cells/L	Standard Deviation 82.4
rFVIIa 90 mcg/kg	Haematology: Platelet Count	Screening	259.0 10^9 cells/L	Standard Deviation 86.1
rFVIIa 90 mcg/kg	Haematology: Platelet Count	12 hours post-dose	260.7 10^9 cells/L	Standard Deviation 69.4

Secondary

Haematology: Red Cell Count

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.1 10^12 cells/L	Standard Deviation 0.5
Vatreptacog Alfa 5 mcg/kg	Haematology: Red Cell Count	Screening	5.0 10^12 cells/L	Standard Deviation 0.5
Vatreptacog Alfa 5 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	5.0 10^12 cells/L	Standard Deviation 0.7
Vatreptacog Alfa 10 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.1 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 10 mcg/kg	Haematology: Red Cell Count	Screening	5.4 10^12 cells/L	Standard Deviation 0.9
Vatreptacog Alfa 10 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	4.9 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 20 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.2 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 20 mcg/kg	Haematology: Red Cell Count	Screening	5.3 10^12 cells/L	Standard Deviation 1
Vatreptacog Alfa 20 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	4.9 10^12 cells/L	Standard Deviation 0.3
Vatreptacog Alfa 40 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.1 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 40 mcg/kg	Haematology: Red Cell Count	Screening	5.1 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 40 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	4.8 10^12 cells/L	Standard Deviation 0.5
Vatreptacog Alfa 80 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.1 10^12 cells/L	Standard Deviation 0.4
Vatreptacog Alfa 80 mcg/kg	Haematology: Red Cell Count	Screening	5.7 10^12 cells/L	Standard Deviation 1.2
Vatreptacog Alfa 80 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	4.9 10^12 cells/L	Standard Deviation 0.3
rFVIIa 90 mcg/kg	Haematology: Red Cell Count	Screening	5.3 10^12 cells/L	Standard Deviation 1
rFVIIa 90 mcg/kg	Haematology: Red Cell Count	12 hours post-dose	5.0 10^12 cells/L	Standard Deviation 0.6
rFVIIa 90 mcg/kg	Haematology: Red Cell Count	Pre-dose	5.2 10^12 cells/L	Standard Deviation 0.5

Secondary

Haematology: White Cell Count

Time frame: screening visit, pre-dose and 12 hours after dosing

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Haematology: White Cell Count	Pre-dose	7.6 10^9 cells/L	Standard Deviation 2.3
Vatreptacog Alfa 5 mcg/kg	Haematology: White Cell Count	Screening	6.7 10^9 cells/L	Standard Deviation 1.9
Vatreptacog Alfa 5 mcg/kg	Haematology: White Cell Count	12 hours post-dose	7.7 10^9 cells/L	Standard Deviation 3.4
Vatreptacog Alfa 10 mcg/kg	Haematology: White Cell Count	Pre-dose	7.3 10^9 cells/L	Standard Deviation 2.6
Vatreptacog Alfa 10 mcg/kg	Haematology: White Cell Count	Screening	6.3 10^9 cells/L	Standard Deviation 2.5
Vatreptacog Alfa 10 mcg/kg	Haematology: White Cell Count	12 hours post-dose	7.2 10^9 cells/L	Standard Deviation 2.1
Vatreptacog Alfa 20 mcg/kg	Haematology: White Cell Count	Pre-dose	7.8 10^9 cells/L	Standard Deviation 1.9
Vatreptacog Alfa 20 mcg/kg	Haematology: White Cell Count	Screening	7.2 10^9 cells/L	Standard Deviation 2.4
Vatreptacog Alfa 20 mcg/kg	Haematology: White Cell Count	12 hours post-dose	8.2 10^9 cells/L	Standard Deviation 2
Vatreptacog Alfa 40 mcg/kg	Haematology: White Cell Count	Pre-dose	7.1 10^9 cells/L	Standard Deviation 2.2
Vatreptacog Alfa 40 mcg/kg	Haematology: White Cell Count	Screening	6.9 10^9 cells/L	Standard Deviation 2.7
Vatreptacog Alfa 40 mcg/kg	Haematology: White Cell Count	12 hours post-dose	7.3 10^9 cells/L	Standard Deviation 2.6
Vatreptacog Alfa 80 mcg/kg	Haematology: White Cell Count	Pre-dose	7.1 10^9 cells/L	Standard Deviation 2.3
Vatreptacog Alfa 80 mcg/kg	Haematology: White Cell Count	Screening	6.6 10^9 cells/L	Standard Deviation 1.5
Vatreptacog Alfa 80 mcg/kg	Haematology: White Cell Count	12 hours post-dose	6.8 10^9 cells/L	Standard Deviation 1.4
rFVIIa 90 mcg/kg	Haematology: White Cell Count	Screening	5.8 10^9 cells/L	Standard Deviation 1.8
rFVIIa 90 mcg/kg	Haematology: White Cell Count	12 hours post-dose	7.1 10^9 cells/L	Standard Deviation 2.5
rFVIIa 90 mcg/kg	Haematology: White Cell Count	Pre-dose	6.5 10^9 cells/L	Standard Deviation 2.1

Secondary

Immunogenicity (Inhibitor Development)

Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or rFVIIa.

Time frame: Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product.

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.

Arm	Measure	Value (NUMBER)
Vatreptacog Alfa 5 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants
Vatreptacog Alfa 10 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants
Vatreptacog Alfa 20 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants
Vatreptacog Alfa 40 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants
Vatreptacog Alfa 80 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants
rFVIIa 90 mcg/kg	Immunogenicity (Inhibitor Development)	0 participants

Secondary

Number of Subjects With Need for Additional Haemostatic Agents

Time frame: within 24 hours after successful control of bleeding episode with trial product

Population: All randomised patients for whom at least one of the efficacy variables is assessed were to be included in the full analysis set (FAS). For the outcome measure 9 subjects did not contribute to the data.

Arm	Measure	Value (NUMBER)
Vatreptacog Alfa 5 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	4 participants
Vatreptacog Alfa 10 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	1 participants
Vatreptacog Alfa 20 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	1 participants
Vatreptacog Alfa 40 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	1 participants
Vatreptacog Alfa 80 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	1 participants
rFVIIa 90 mcg/kg	Number of Subjects With Need for Additional Haemostatic Agents	1 participants

Secondary

Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)

Time frame: 0-24 hours after trial product administration

Population: All randomised patients in top 3 dosing tiers 3, 4 and 5 who had pharmacokinetic assessments and completed the trial without violating the protocol in a manner that was judged to affect the pharmacokinetic endpoints were included in the pharmacokinetic analysis set. Some subjects did not contribute for pharmacokinetic analysis.

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Vatreptacog Alfa 20 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)	35.76 (IU*h)/mL	Geometric Coefficient of Variation 26.34
Vatreptacog Alfa 40 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)	71.23 (IU*h)/mL	Geometric Coefficient of Variation 55.42
Vatreptacog Alfa 80 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)	139.63 (IU*h)/mL	Geometric Coefficient of Variation 18.35
rFVIIa 90 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)	101.38 (IU*h)/mL	Geometric Coefficient of Variation 40.77

Secondary

Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )

Time frame: 0-24 hours after trial product administration

Arm	Measure	Value (GEOMETRIC_MEAN)	Dispersion
Vatreptacog Alfa 20 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )	34.24 (IU*h)/mL	Geometric Coefficient of Variation 27
Vatreptacog Alfa 40 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )	66.85 (IU*h)/mL	Geometric Coefficient of Variation 50.51
Vatreptacog Alfa 80 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )	136.19 (IU*h)/mL	Geometric Coefficient of Variation 18.56
rFVIIa 90 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )	74.35 (IU*h)/mL	Geometric Coefficient of Variation 45.3

Secondary

Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)

Time frame: 0-24 hours after trial product administration

Arm	Measure	Value (MEDIAN)
Vatreptacog Alfa 20 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)	9365.8 mL/h
Vatreptacog Alfa 40 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)	11247 mL/h
Vatreptacog Alfa 80 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)	10409 mL/h
rFVIIa 90 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)	3078.3 mL/h

Secondary

Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)

Time frame: 0-24 hours after trial product administration

Arm	Measure	Value (MEAN)	Dispersion
Vatreptacog Alfa 20 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)	0.68 hours	Standard Deviation 0.16
Vatreptacog Alfa 40 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)	0.88 hours	Standard Deviation 0.33
Vatreptacog Alfa 80 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)	0.56 hours	Standard Deviation 0.1
rFVIIa 90 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)	2.23 hours	Standard Deviation 0.54

Secondary

Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)

Time frame: 0-24 hours after trial product administration

Arm	Measure	Value (MEAN)	Dispersion
Vatreptacog Alfa 20 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)	0.92 hours	Standard Deviation 0.18
Vatreptacog Alfa 40 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)	1.28 hours	Standard Deviation 1.28
Vatreptacog Alfa 80 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)	0.71 hours	Standard Deviation 0.16
rFVIIa 90 mcg/kg	Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)	1.66 hours	Standard Deviation 0.35

Secondary

Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)

Time frame: 0-24 hours after trial product administration

Arm	Measure	Value (MEDIAN)
Vatreptacog Alfa 20 mcg/kg	Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)	5396.9 mL/kg
Vatreptacog Alfa 40 mcg/kg	Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)	9597.0 mL/kg
Vatreptacog Alfa 80 mcg/kg	Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)	5538.7 mL/kg
rFVIIa 90 mcg/kg	Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)	6696.7 mL/kg

Secondary

Prothrombin Time (PT)

The test measures the clotting time of plasma following the activation of tissue factor (TF also called thromboplastin) and calcium to hypocalcemic plasma. PT was provided in percent based on the measured PT in seconds and related/converted with the relevant standard curve. The percent value was derived based on the hyperbolic relation between PT (sec) and % PT activity.

Time frame: pre-dose - 12 hours after trial product administration

Population: Safety analysis set includes all subjects who received at least one dose of the investigational product or its comparator.

Arm	Measure	Group	Value (MEAN)	Dispersion
Vatreptacog Alfa 5 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	84.3 percentage (%)	Standard Deviation 16.3
Vatreptacog Alfa 5 mcg/kg	Prothrombin Time (PT)	Pre-dose	80.1 percentage (%)	Standard Deviation 12.6
Vatreptacog Alfa 5 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	82.1 percentage (%)	Standard Deviation 16.2
Vatreptacog Alfa 10 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	99.6 percentage (%)	Standard Deviation 17.9
Vatreptacog Alfa 10 mcg/kg	Prothrombin Time (PT)	Pre-dose	77.6 percentage (%)	Standard Deviation 19.1
Vatreptacog Alfa 10 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	73.2 percentage (%)	Standard Deviation 19.2
Vatreptacog Alfa 20 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	112.1 percentage (%)	Standard Deviation 14.6
Vatreptacog Alfa 20 mcg/kg	Prothrombin Time (PT)	Pre-dose	79.1 percentage (%)	Standard Deviation 14.9
Vatreptacog Alfa 20 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	86.9 percentage (%)	Standard Deviation 14.1
Vatreptacog Alfa 40 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	123.4 percentage (%)	Standard Deviation 14.7
Vatreptacog Alfa 40 mcg/kg	Prothrombin Time (PT)	Pre-dose	85.9 percentage (%)	Standard Deviation 15.5
Vatreptacog Alfa 40 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	94.5 percentage (%)	Standard Deviation 17.5
Vatreptacog Alfa 80 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	128.5 percentage (%)	Standard Deviation 7.6
Vatreptacog Alfa 80 mcg/kg	Prothrombin Time (PT)	Pre-dose	85.5 percentage (%)	Standard Deviation 8.8
Vatreptacog Alfa 80 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	92.3 percentage (%)	Standard Deviation 16.8
rFVIIa 90 mcg/kg	Prothrombin Time (PT)	Pre-dose	88.3 percentage (%)	Standard Deviation 25.6
rFVIIa 90 mcg/kg	Prothrombin Time (PT)	12 hours post-dose	112.1 percentage (%)	Standard Deviation 29.1
rFVIIa 90 mcg/kg	Prothrombin Time (PT)	1 hours post-dose	139.0 percentage (%)	Standard Deviation 0

Source: ClinicalTrials.gov · Data processed: Mar 27, 2026

Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

Conditions

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Number of Adverse Events (AEs)

Activated Partial Thromboplastin Time (aPTT)

Activated Recombinant Human Factor VII Analogue Activity in the Blood

Biochemistry: ALAT (Alanine Aminotransferase)

Biochemistry: Creatinine

Cessation of Bleeding: Number of Doses Needed to Control Bleeding

F1 + 2 (Prothrombin Fragments 1+2)

Haematology: Haemoglobin

Haematology: Packed Cell Volume

Haematology: Platelet Count

Haematology: Red Cell Count

Haematology: White Cell Count

Immunogenicity (Inhibitor Development)

Number of Subjects With Need for Additional Haemostatic Agents

Pharmacokinetic Parameters Based on FVIIa Activity: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)

Pharmacokinetic Parameters Based on FVIIa Activity: AUC 0-t (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to the Time (t) )

Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)

Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)

Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)

Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)

Prothrombin Time (PT)