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Safety and Efficacy of NNC-0156-0000-0009 in Haemophilia B Patients (paradigm™ 2)

Primary Purpose

Congenital Bleeding Disorder, Haemophilia B

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
nonacog beta pegol
nonacog beta pegol
nonacog beta pegol
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

13 Years - 70 Years (Child, Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Male patients with moderately severe or severe congenital haemophilia B with a factor IX activity of 2% or below according to medical records
  • History of at least 150 exposure days to other factor IX products
  • Patients currently treated on-demand with at least 6 bleeding episodes during the last 12 months or at least 3 bleeding episodes during the last 6 months, or patients currently on prophylaxis

Exclusion Criteria:

  • Known history of factor IX inhibitors based on existing medical records, laboratory report reviews and patient and legally acceptable representative (LAR) interviews
  • HIV (Human immunodeficiency virus) positive, with a viral load equal to or above 400,000 copies/mL and/or CD4+ lymphocyte count equal to or below 200/microL
  • Congenital or acquired coagulation disorders other than haemophilia B
  • Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records)
  • Immune modulating or chemotherapeutic medication

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Experimental

Experimental

Arm Label

Prophylaxis, high dose (trial duration 52 weeks)

Prophylaxis, low dose (trial duration 52 weeks)

On-demand (trial duration 28 weeks)

Arm Description

Outcomes

Primary Outcome Measures

Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.

Secondary Outcome Measures

Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Number of Bleeding Episodes Per Patient During Routine Prophylaxis
The number of bleeding episodes per patient during routine prophylaxis was assessed using the individual annualised bleeding rates (spontaneous and traumatic bleeding episodes per patient per year).
Factor IX Trough Levels
The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Lowest factor IX activity recorded during single-dose and steady state, immediately before next dose was given. The analysis was based on a mixed model on the log-transformed plasma factor IX activity with subject as a random effect. The estimated mean factor IX trough level was presented back-transformed to the natural scale.
Incidence of Adverse Events (AEs)
The incidence of adverse events were summarised by the rate of AEs (number of AEs per patient years of exposure [PYE]). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Incidence of Adverse Events (AEs)
The incidence of adverse events were summarised by the rate of AEs (number of AEs per PYE). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Incidence of Serious Adverse Events (SAEs)
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Incidence of Serious Adverse Events (SAEs)
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Host Cell Proteins (HCP) Antibodies
Subjects who were positive for anti-Host Cell Protein (HCP) antibodies.
Host Cell Proteins (HCP) Antibodies
Subjects who were positive for anti-HCP antibodies.

Full Information

First Posted
April 8, 2011
Last Updated
June 27, 2017
Sponsor
Novo Nordisk A/S
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1. Study Identification

Unique Protocol Identification Number
NCT01333111
Brief Title
Safety and Efficacy of NNC-0156-0000-0009 in Haemophilia B Patients
Acronym
paradigm™ 2
Official Title
A Multi-centre, Single-blind Trial Evaluating Safety and Efficacy, Including Pharmacokinetics, of NNC-0156-0000-0009 When Used for Treatment and Prophylaxis of Bleeding Episodes in Patients With Haemophilia B
Study Type
Interventional

2. Study Status

Record Verification Date
June 2017
Overall Recruitment Status
Completed
Study Start Date
April 27, 2011 (Actual)
Primary Completion Date
March 31, 2013 (Actual)
Study Completion Date
March 31, 2013 (Actual)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
This trial is conducted in Africa, Asia, Europe, Japan and North America. The aim of this trial is to evaluate the safety and efficacy, including pharmacokinetics (the rate at which the body eliminates the trial drug), of NNC-0156-0000-0009 (nonacog beta pegol) when used for treatment and prophylaxis of bleeding episodes in patients with haemophilia B.

6. Conditions and Keywords

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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
74 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Prophylaxis, high dose (trial duration 52 weeks)
Arm Type
Experimental
Arm Title
Prophylaxis, low dose (trial duration 52 weeks)
Arm Type
Experimental
Arm Title
On-demand (trial duration 28 weeks)
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
nonacog beta pegol
Other Intervention Name(s)
NNC-0156-0000-0009
Intervention Description
One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience
Intervention Type
Drug
Intervention Name(s)
nonacog beta pegol
Other Intervention Name(s)
NNC-0156-0000-0009
Intervention Description
One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience
Intervention Type
Drug
Intervention Name(s)
nonacog beta pegol
Other Intervention Name(s)
NNC-0156-0000-0009
Intervention Description
Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode
Primary Outcome Measure Information:
Title
Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Description
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
Time Frame
52 weeks after treatment start for patients on prophylaxis
Title
Incidence of Inhibitory Antibodies Against Factor IX Defined as Titre Equal to or Above 0.6 BU (Bethesda Units)
Description
Inhibitors were analysed with either the Nijmegen modified factor IX Bethesda assay or a heat/cold Nijmegen modified factor IX Bethesda assay. Number of subjects who developed inhibitory antibodies against factor IX are reported.
Time Frame
28 weeks after treatment start on on-demand treatment
Secondary Outcome Measure Information:
Title
Haemostatic Effect of NNC-0156-0000-0009 When Used for Prophylaxis of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Description
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Time Frame
52 weeks after treatment start for patients on prophylaxis
Title
Haemostatic Effect of NNC-0156-0000-0009 When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response
Description
Haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4 point scale as excellent, good, moderate or poor. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures. Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single injection Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one injection within 8 hours Poor - no improvement, or worsening of symptoms within 8 hours after two injections. The success rate and 95% confidence interval (CI) are reported here.
Time Frame
28 weeks after treatment start on on-demand treatment
Title
Number of Bleeding Episodes Per Patient During Routine Prophylaxis
Description
The number of bleeding episodes per patient during routine prophylaxis was assessed using the individual annualised bleeding rates (spontaneous and traumatic bleeding episodes per patient per year).
Time Frame
52 weeks after treatment start for patients on prophylaxis
Title
Factor IX Trough Levels
Description
The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Lowest factor IX activity recorded during single-dose and steady state, immediately before next dose was given. The analysis was based on a mixed model on the log-transformed plasma factor IX activity with subject as a random effect. The estimated mean factor IX trough level was presented back-transformed to the natural scale.
Time Frame
52 weeks after treatment start for patients on prophylaxis
Title
Incidence of Adverse Events (AEs)
Description
The incidence of adverse events were summarised by the rate of AEs (number of AEs per patient years of exposure [PYE]). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Time Frame
at 56 weeks ±2 weeks for patients on prophylaxis
Title
Incidence of Adverse Events (AEs)
Description
The incidence of adverse events were summarised by the rate of AEs (number of AEs per PYE). Number of adverse events per PYE is number of adverse events /total time in trial. All adverse events reported are treatment emergent (any adverse events which occurred after trial product administration).
Time Frame
at 32 weeks ±2 weeks for patients on on-demand treatment
Title
Incidence of Serious Adverse Events (SAEs)
Description
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Time Frame
at 56 weeks ±2 weeks for patients on prophylaxis
Title
Incidence of Serious Adverse Events (SAEs)
Description
SAE was defined as an AE that resulted in any of the following: death, a life-threatening experience, in-subject hospitalization/prolongation of existing hospitalisation, persistent/significant disability/incapacity/congenital anomaly/birth defect. The incidence of SAEs were summarised by the rate of SAEs (number of SAEs per PYE). Number of SAEs per PYE is number of SAEs/total time in trial. All SAEs reported are treatment emergent (any serious adverse events which occurred after trial product administration).
Time Frame
at 32 weeks ±2 weeks for patients on on-demand treatment
Title
Host Cell Proteins (HCP) Antibodies
Description
Subjects who were positive for anti-Host Cell Protein (HCP) antibodies.
Time Frame
52 weeks after treatment start for patients on prophylaxis
Title
Host Cell Proteins (HCP) Antibodies
Description
Subjects who were positive for anti-HCP antibodies.
Time Frame
28 weeks after treatment start on on-demand treatment

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
13 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male patients with moderately severe or severe congenital haemophilia B with a factor IX activity of 2% or below according to medical records History of at least 150 exposure days to other factor IX products Patients currently treated on-demand with at least 6 bleeding episodes during the last 12 months or at least 3 bleeding episodes during the last 6 months, or patients currently on prophylaxis Exclusion Criteria: Known history of factor IX inhibitors based on existing medical records, laboratory report reviews and patient and legally acceptable representative (LAR) interviews HIV (Human immunodeficiency virus) positive, with a viral load equal to or above 400,000 copies/mL and/or CD4+ lymphocyte count equal to or below 200/microL Congenital or acquired coagulation disorders other than haemophilia B Previous arterial thrombotic events (e.g. myocardial infarction and intracranial thrombosis) or previous deep venous thrombosis or pulmonary embolism (as defined by available medical records) Immune modulating or chemotherapeutic medication
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
90027-6016
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Jacksonville
State/Province
Florida
ZIP/Postal Code
32207
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
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21287
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55404
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198-5456
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Newark
State/Province
New Jersey
ZIP/Postal Code
07102
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
Syracuse
State/Province
New York
ZIP/Postal Code
13210
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Hershey
State/Province
Pennsylvania
ZIP/Postal Code
17033
Country
United States
Facility Name
Novo Nordisk Investigational Site
City
Houston
State/Province
Texas
ZIP/Postal Code
77030
Country
United States
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
Kremlin-Bicêtre
ZIP/Postal Code
94270
Country
France
Facility Name
Novo Nordisk Investigational Site
City
Lyon
ZIP/Postal Code
69003
Country
France
Facility Name
Novo Nordisk Investigational Site
City
Bonn
ZIP/Postal Code
53127
Country
Germany
Facility Name
Novo Nordisk Investigational Site
City
Duisburg
ZIP/Postal Code
47051
Country
Germany
Facility Name
Novo Nordisk Investigational Site
City
Giessen
ZIP/Postal Code
35392
Country
Germany
Facility Name
Novo Nordisk Investigational Site
City
Hannover
ZIP/Postal Code
30625
Country
Germany
Facility Name
Novo Nordisk Investigational Site
City
Budapest
ZIP/Postal Code
H-1134
Country
Hungary
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
Kawasaki-shi, Kanagawa
ZIP/Postal Code
216-8511
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
Shinjuku-ku, Tokyo
ZIP/Postal Code
160 0023
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Suginami-ku, Tokyo
ZIP/Postal Code
167 0035
Country
Japan
Facility Name
Novo Nordisk Investigational Site
City
Skopje
ZIP/Postal Code
1000
Country
Macedonia, The Former Yugoslav Republic of
Facility Name
Novo Nordisk Investigational Site
City
Kuala Lumpur
ZIP/Postal Code
50400
Country
Malaysia
Facility Name
Novo Nordisk Investigational Site
City
Utrecht
ZIP/Postal Code
3584 CX
Country
Netherlands
Facility Name
Novo Nordisk Investigational Site
City
Moscow
ZIP/Postal Code
105077
Country
Russian Federation
Facility Name
Novo Nordisk Investigational Site
City
Saint-Petersburg
ZIP/Postal Code
191119
Country
Russian Federation
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
Bangkok
ZIP/Postal Code
10400
Country
Thailand
Facility Name
Novo Nordisk Investigational Site
City
Ankara
ZIP/Postal Code
06500
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Kayseri
ZIP/Postal Code
38010
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Konya
ZIP/Postal Code
42090
Country
Turkey
Facility Name
Novo Nordisk Investigational Site
City
Basingstoke
ZIP/Postal Code
RG24 9NA
Country
United Kingdom
Facility Name
Novo Nordisk Investigational Site
City
Cardiff
ZIP/Postal Code
CF14 4XW
Country
United Kingdom
Facility Name
Novo Nordisk Investigational Site
City
London
ZIP/Postal Code
NW3 2QG
Country
United Kingdom
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
Facility Name
Novo Nordisk Investigational Site
City
Oxford
ZIP/Postal Code
OX3 7LJ
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
25261199
Citation
Collins PW, Young G, Knobe K, Karim FA, Angchaisuksiri P, Banner C, Gursel T, Mahlangu J, Matsushita T, Mauser-Bunschoten EP, Oldenburg J, Walsh CE, Negrier C; paradigm 2 Investigators. Recombinant long-acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 2014 Dec 18;124(26):3880-6. doi: 10.1182/blood-2014-05-573055. Epub 2014 Sep 26.
Results Reference
background
Links:
URL
http://novonordisk-trials.com
Description
Clinical Trials at Novo Nordisk

Learn more about this trial

Safety and Efficacy of NNC-0156-0000-0009 in Haemophilia B Patients

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