Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Congenital Bleeding Disorder, Haemophilia A, Haemophilia B

Intervention / Treatment
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* Drug: eptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)
* Drug: vatreptacog alfa (activated)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: vatreptacog alfa 5 mcg/kg<br> | Drug: vatreptacog alfa (activated)<br>* 5 mcg/kg, injected i.v.<br>|
| Experimental: vatreptacog alfa 10 mcg/kg<br> | Drug: vatreptacog alfa (activated)<br>* 10 mcg/kg, injected i.v.<br>|
| Experimental: vatreptacog alfa 20 mcg/kg<br> | Drug: vatreptacog alfa (activated)<br>* 20 mcg/kg, injected i.v.<br>|
| Experimental: vatreptacog alfa 40 mcg/kg<br> | Drug: vatreptacog alfa (activated)<br>* 40 mcg/kg, injected i.v.<br>|
| Experimental: vatreptacog alfa 80 mcg/kg<br> | Drug: vatreptacog alfa (activated)<br>* 80 mcg/kg, injected i.v.<br>|
| Experimental: rFVIIa 90 mcg/kg<br> | Drug: eptacog alfa (activated)<br>* 90 mcg/kg, injected i.v.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activated Recombinant Human Factor VII Analogue Activity in the Blood |  | 0-24 hours after trial product administration | 
| 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. | pre-dose - 12 hours after trial product administration | 
| 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. | pre-dose - 12 hours after trial product administration | 
| 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. | pre-dose - 12 hours after trial product administration | 
| 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) | Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or rFVIIa. | Monitoring of adverse events was performed from start of the trial to approximately 4 weeks after administration of trial product. | 
| 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 | 
| Haematology: White Cell Count |  | screening visit, pre-dose and 12 hours after dosing | 
| Haematology: Platelet Count |  | screening visit, pre-dose and 12 hours after dosing |