Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

Phase 2

Completed

Conditions: Congenital Bleeding Disorder
Haemophilia A
Haemophilia B

Interventions: Drug: vatreptacog alfa (activated)
Drug: eptacog alfa (activated)

Registration Number: NCT00486278

Lead Sponsor: Novo Nordisk A/S

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.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: Male

Target Recruitment: 51

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
vatreptacog alfa 5 mcg/kg	vatreptacog alfa (activated)	-
vatreptacog alfa 10 mcg/kg	vatreptacog alfa (activated)	-
vatreptacog alfa 40 mcg/kg	vatreptacog alfa (activated)	-
rFVIIa 90 mcg/kg	eptacog alfa (activated)	-
vatreptacog alfa 20 mcg/kg	vatreptacog alfa (activated)	-
vatreptacog alfa 80 mcg/kg	vatreptacog alfa (activated)	-

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
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.
Biochemistry: ALAT (Alanine Aminotransferase)	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
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
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)
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.
Haematology: Packed Cell Volume	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: Platelet Count	screening visit, pre-dose and 12 hours after dosing
Haematology: Red Cell Count	screening visit, pre-dose and 12 hours after dosing
Haematology: White Cell Count	screening visit, pre-dose and 12 hours after dosing