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

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.

Study Overview

• Status: Completed
• Conditions: Congenital Bleeding Disorder; Haemophilia A; Haemophilia B
• Intervention / Treatment: Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: vatreptacog alfa (activated); Drug: eptacog alfa (activated)

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autónoma de Bs. As., Argentina, C1425ASU
    • Novo Nordisk Investigational Site
• Brazil
  • Rio de Janeiro, Brazil, 20211-030
    • Novo Nordisk Investigational Site
  • São Paulo, Brazil, 04024-002
    • Novo Nordisk Investigational Site
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13081970
      • Novo Nordisk Investigational Site
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novo Nordisk Investigational Site
• Croatia
  • Zagreb, Croatia, 10 000
    • Novo Nordisk Investigational Site
• France
  • Lyon, France, 69003
    • Novo Nordisk Investigational Site
• Hungary
  • Budapest, Hungary, H-1134
    • Novo Nordisk Investigational Site
  • Debrecen, Hungary, 4012
    • Novo Nordisk Investigational Site
• Israel
  • Tel-Hashomer, Israel, 52621
    • Novo Nordisk Investigational Site
• Italy
  • Castelfranco Veneto, Italy, 31033
    • Novo Nordisk Investigational Site
  • Firenze, Italy, 50134
    • Novo Nordisk Investigational Site
  • Milano, Italy, 20124
    • Novo Nordisk Investigational Site
• Japan
  • Hiroshima-shi, Hiroshima, Japan, 734 8551
    • Novo Nordisk Investigational Site
  • Itabashi-ku, Tokyo, Japan, 173 8606
    • Novo Nordisk Investigational Site
  • Kashihara-shi, Nara, Japan, 634 8522
    • Novo Nordisk Investigational Site
  • Nagoya-shi, Aichi, Japan, 466 8560
    • Novo Nordisk Investigational Site
  • Nishinomiya-shi, Japan, 663 8051
    • Novo Nordisk Investigational Site
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Novo Nordisk Investigational Site
• Poland
  • Warszawa, Poland, 02-776
    • Novo Nordisk Investigational Site
• South Africa
  • Cape Town, South Africa, 7925
    • Novo Nordisk Investigational Site
  • Gauteng
    • Parktown Johannesburg, Gauteng, South Africa, 2193
      • Novo Nordisk Investigational Site
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4013
      • Novo Nordisk Investigational Site
• Spain
  • Madrid, Spain, 28046
    • Novo Nordisk Investigational Site
• Taiwan
  • Changhua, Taiwan, 500
    • Novo Nordisk Investigational Site
  • Taipei, Taiwan, 100
    • Novo Nordisk Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novo Nordisk Investigational Site
• Turkey
  • Adana, Turkey, 01130
    • Novo Nordisk Investigational Site
  • Ankara, Turkey, 06100
    • Novo Nordisk Investigational Site
  • Antalya, Turkey, 01010
    • Novo Nordisk Investigational Site
  • Bornova-IZMIR, Turkey, 35100
    • Novo Nordisk Investigational Site
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M13 9WL
    • Novo Nordisk Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Novo Nordisk Investigational Site
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Novo Nordisk Investigational Site
  • Illinois
    • Chicago, Illinois, United States, 60612-3833
      • Novo Nordisk Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Novo Nordisk Investigational Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Novo Nordisk Investigational Site
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Novo Nordisk Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5235
      • Novo Nordisk Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Novo Nordisk Investigational Site
  • New York
    • New York, New York, United States, 10029
      • Novo Nordisk Investigational Site
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599-7035
      • Novo Nordisk Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Novo Nordisk Investigational Site
  • Oregon
    • Portland, Oregon, United States, 97239-3011
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• de Paula EV, Kavakli K, Mahlangu J, Ayob Y, Lentz SR, Morfini M, Nemes L, Salek SZ, Shima M, Windyga J, Ehrenforth S, Chuansumrit A; 1804 (adept(TM)1) Investigators. Recombinant factor VIIa analog (vatreptacog alfa [activated]) for treatment of joint bleeds in hemophilia patients with inhibitors: a randomized controlled trial. J Thromb Haemost. 2012 Jan;10(1):81-9. doi: 10.1111/j.1538-7836.2011.04549.x.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start: June 1, 2007
• Primary Completion (Actual): June 1, 2010
• Study Completion (Actual): June 1, 2010

Study Registration Dates

• First Submitted: June 13, 2007
• First Submitted That Met QC Criteria: June 13, 2007
• First Posted (Estimate): June 14, 2007

Study Record Updates

• Last Update Posted (Actual): March 7, 2017
• Last Update Submitted That Met QC Criteria: January 23, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Hemostatic Disorders; Hemophilia A; Hemophilia B; Blood Coagulation Disorders
• Other Study ID Numbers: NN1731-1804; 2006-004879-35 (EudraCT Number); CTI-080612 (Other Identifier: JAPIC)