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Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

Primary Purpose

Congenital Bleeding Disorder, Haemophilia A, Haemophilia B

Status
Completed
Phase
Phase 2
Locations
International
Study Type
Interventional
Intervention
eptacog alfa (activated)
vatreptacog alfa (activated)
vatreptacog alfa (activated)
vatreptacog alfa (activated)
vatreptacog alfa (activated)
vatreptacog alfa (activated)
Sponsored by
Novo Nordisk A/S
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Congenital Bleeding Disorder

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)MaleDoes not accept 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

Sites / Locations

  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site
  • Novo Nordisk Investigational Site

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

vatreptacog alfa 5 mcg/kg

vatreptacog alfa 10 mcg/kg

vatreptacog alfa 20 mcg/kg

vatreptacog alfa 40 mcg/kg

vatreptacog alfa 80 mcg/kg

rFVIIa 90 mcg/kg

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Activated Recombinant Human Factor VII Analogue Activity in the Blood
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.
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.
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.
Cessation of Bleeding: Number of Doses Needed to Control Bleeding
Number of Subjects With Need for Additional Haemostatic Agents
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: AUC(0-inf) (Area Under the Plasma FVIIa Activity-time Curve From Time Zero to Infinity)
Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)
Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)
Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)
Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)
Immunogenicity (Inhibitor Development)
Immunogenicity was tested by formation of neutralising antibodies towards vatreptacog alfa and/or rFVIIa.
Biochemistry: ALAT (Alanine Aminotransferase)
Biochemistry: Creatinine
Haematology: Haemoglobin
Haematology: Red Cell Count
Haematology: Packed Cell Volume
Haematology: White Cell Count
Haematology: Platelet Count

Full Information

First Posted
June 13, 2007
Last Updated
January 23, 2017
Sponsor
Novo Nordisk A/S
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1. Study Identification

Unique Protocol Identification Number
NCT00486278
Brief Title
Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
June 2007 (undefined)
Primary Completion Date
June 2010 (Actual)
Study Completion Date
June 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novo Nordisk A/S

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Congenital Bleeding Disorder, Haemophilia A, Haemophilia B

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
51 (Actual)

8. Arms, Groups, and Interventions

Arm Title
vatreptacog alfa 5 mcg/kg
Arm Type
Experimental
Arm Title
vatreptacog alfa 10 mcg/kg
Arm Type
Experimental
Arm Title
vatreptacog alfa 20 mcg/kg
Arm Type
Experimental
Arm Title
vatreptacog alfa 40 mcg/kg
Arm Type
Experimental
Arm Title
vatreptacog alfa 80 mcg/kg
Arm Type
Experimental
Arm Title
rFVIIa 90 mcg/kg
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
eptacog alfa (activated)
Intervention Description
90 mcg/kg, injected i.v.
Intervention Type
Drug
Intervention Name(s)
vatreptacog alfa (activated)
Intervention Description
5 mcg/kg, injected i.v.
Intervention Type
Drug
Intervention Name(s)
vatreptacog alfa (activated)
Intervention Description
10 mcg/kg, injected i.v.
Intervention Type
Drug
Intervention Name(s)
vatreptacog alfa (activated)
Intervention Description
20 mcg/kg, injected i.v.
Intervention Type
Drug
Intervention Name(s)
vatreptacog alfa (activated)
Intervention Description
40 mcg/kg, injected i.v.
Intervention Type
Drug
Intervention Name(s)
vatreptacog alfa (activated)
Intervention Description
80 mcg/kg, injected i.v.
Primary Outcome Measure Information:
Title
Number of Adverse Events (AEs)
Description
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.
Secondary Outcome Measure Information:
Title
Activated Recombinant Human Factor VII Analogue Activity in the Blood
Time Frame
0-24 hours after trial product administration
Title
Prothrombin Time (PT)
Description
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
Title
F1 + 2 (Prothrombin Fragments 1+2)
Description
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
Title
Activated Partial Thromboplastin Time (aPTT)
Description
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
Title
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)
Title
Number of Subjects With Need for Additional Haemostatic Agents
Time Frame
within 24 hours after successful control of bleeding episode with trial product
Title
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
Title
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
Title
Pharmacokinetic Parameters Based on FVIIa Activity: MRT (Mean Residence Time)
Time Frame
0-24 hours after trial product administration
Title
Pharmacokinetic Parameters Based on FVIIa Activity: t½ (Terminal Half-life)
Time Frame
0-24 hours after trial product administration
Title
Pharmacokinetic Parameters Based on FVIIa Activity: CL (Total Clearance)
Time Frame
0-24 hours after trial product administration
Title
Pharmakokinetic Parameters Based on FVIIa Activity: Vss (Distribution Volume at Steady State)
Time Frame
0-24 hours after trial product administration
Title
Immunogenicity (Inhibitor Development)
Description
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.
Title
Biochemistry: ALAT (Alanine Aminotransferase)
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Biochemistry: Creatinine
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Haematology: Haemoglobin
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Haematology: Red Cell Count
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Haematology: Packed Cell Volume
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Haematology: White Cell Count
Time Frame
screening visit, pre-dose and 12 hours after dosing
Title
Haematology: Platelet Count
Time Frame
screening visit, pre-dose and 12 hours after dosing

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Global Clinical Registry (GCR, 1452)
Organizational Affiliation
Novo Nordisk A/S
Official's Role
Study Director
Facility Information:
Facility Name
Novo Nordisk Investigational Site
City
Los Angeles
State/Province
California
ZIP/Postal Code
90027
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Augusta
State/Province
Georgia
ZIP/Postal Code
30912
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612-3833
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Indianapolis
State/Province
Indiana
ZIP/Postal Code
46260
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-5235
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55455
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
New York
State/Province
New York
ZIP/Postal Code
10029
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599-7035
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45229
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Portland
State/Province
Oregon
ZIP/Postal Code
97239-3011
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Ciudad Autónoma de Bs. As.
ZIP/Postal Code
C1425ASU
Country
Argentina
Facility Name
Novo Nordisk Investigational Site
City
Campinas
State/Province
Sao Paulo
ZIP/Postal Code
13081970
Country
Brazil
Facility Name
Novo Nordisk Investigational Site
City
Rio de Janeiro
ZIP/Postal Code
20211-030
Country
Brazil
Facility Name
Novo Nordisk Investigational Site
City
São Paulo
ZIP/Postal Code
04024-002
Country
Brazil
Facility Name
Novo Nordisk Investigational Site
City
Edmonton
State/Province
Alberta
ZIP/Postal Code
T6G 2B7
Country
Canada
Facility Name
Novo Nordisk Investigational Site
City
Zagreb
ZIP/Postal Code
10 000
Country
Croatia
Facility Name
Novo Nordisk Investigational Site
City
Lyon
ZIP/Postal Code
69003
Country
France
Facility Name
Novo Nordisk Investigational Site
City
Budapest
ZIP/Postal Code
H-1134
Country
Hungary
Facility Name
Novo Nordisk Investigational Site
City
Debrecen
ZIP/Postal Code
4012
Country
Hungary
Facility Name
Novo Nordisk Investigational Site
City
Tel-Hashomer
ZIP/Postal Code
52621
Country
Israel
Facility Name
Novo Nordisk Investigational Site
City
Castelfranco Veneto
ZIP/Postal Code
31033
Country
Italy
Facility Name
Novo Nordisk Investigational Site
City
Firenze
ZIP/Postal Code
50134
Country
Italy
Facility Name
Novo Nordisk Investigational Site
City
Milano
ZIP/Postal Code
20124
Country
Italy
Facility Name
Novo Nordisk Investigational Site
City
Hiroshima-shi, Hiroshima
ZIP/Postal Code
734 8551
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Itabashi-ku, Tokyo
ZIP/Postal Code
173 8606
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Kashihara-shi, Nara
ZIP/Postal Code
634 8522
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Nagoya-shi, Aichi
ZIP/Postal Code
466 8560
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Nishinomiya-shi
ZIP/Postal Code
663 8051
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Kuala Lumpur
ZIP/Postal Code
50400
Country
Malaysia
Facility Name
Novo Nordisk Investigational Site
City
Warszawa
ZIP/Postal Code
02-776
Country
Poland
Facility Name
Novo Nordisk Investigational Site
City
Parktown Johannesburg
State/Province
Gauteng
ZIP/Postal Code
2193
Country
South Africa
Facility Name
Novo Nordisk Investigational Site
City
Durban
State/Province
KwaZulu-Natal
ZIP/Postal Code
4013
Country
South Africa
Facility Name
Novo Nordisk Investigational Site
City
Cape Town
ZIP/Postal Code
7925
Country
South Africa
Facility Name
Novo Nordisk Investigational Site
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Novo Nordisk Investigational Site
City
Changhua
ZIP/Postal Code
500
Country
Taiwan
Facility Name
Novo Nordisk Investigational Site
City
Taipei
ZIP/Postal Code
100
Country
Taiwan
Facility Name
Novo Nordisk Investigational Site
City
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Novo Nordisk Investigational Site
City
Adana
ZIP/Postal Code
01130
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Ankara
ZIP/Postal Code
06100
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Antalya
ZIP/Postal Code
01010
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Bornova-IZMIR
ZIP/Postal Code
35100
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
London
ZIP/Postal Code
SE1 7EH
Country
United Kingdom
Facility Name
Novo Nordisk Investigational Site
City
Manchester
ZIP/Postal Code
M13 9WL
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
22470921
Citation
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.
Results Reference
result
Links:
URL
http://novonordisk-trials.com
Description
Clinical Trials at Novo Nordisk

Learn more about this trial

Haemophilia Patients With Inhibitors Being Treated for Acute Joint Bleeds

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