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

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

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.

Study Overview

• Status: Completed
• Conditions: Congenital Bleeding Disorder; Haemophilia B
• Intervention / Treatment: Drug: nonacog beta pegol; Drug: nonacog beta pegol

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Novo Nordisk Investigational Site
• France
  • Kremlin-Bicêtre, France, 94270
    • Novo Nordisk Investigational Site
  • Lyon, France, 69003
    • Novo Nordisk Investigational Site
• Germany
  • Bonn, Germany, 53127
    • Novo Nordisk Investigational Site
  • Duisburg, Germany, 47051
    • Novo Nordisk Investigational Site
  • Giessen, Germany, 35392
    • Novo Nordisk Investigational Site
  • Hannover, Germany, 30625
    • Novo Nordisk Investigational Site
• Hungary
  • Budapest, Hungary, H-1134
    • Novo Nordisk Investigational Site
• Italy
  • Firenze, Italy, 50134
    • Novo Nordisk Investigational Site
  • Milano, Italy, 20124
    • Novo Nordisk Investigational Site
• Japan
  • Kawasaki-shi, Kanagawa, Japan, 216-8511
    • Novo Nordisk Investigational Site
  • Nagoya-shi, Aichi, Japan, 466 8560
    • Novo Nordisk Investigational Site
  • Nishinomiya-shi, Japan, 663 8051
    • Novo Nordisk Investigational Site
  • Shinjuku-ku, Tokyo, Japan, 160 0023
    • Novo Nordisk Investigational Site
  • Suginami-ku, Tokyo, Japan, 167 0035
    • Novo Nordisk Investigational Site
• Macedonia, The Former Yugoslav Republic of
  • Skopje, Macedonia, The Former Yugoslav Republic of, 1000
    • Novo Nordisk Investigational Site
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • Novo Nordisk Investigational Site
• Netherlands
  • Utrecht, Netherlands, 3584 CX
    • Novo Nordisk Investigational Site
• Russian Federation
  • Moscow, Russian Federation, 105077
    • Novo Nordisk Investigational Site
  • Saint-Petersburg, Russian Federation, 191119
    • Novo Nordisk Investigational Site
• South Africa
  • Gauteng
    • Parktown Johannesburg, Gauteng, South Africa, 2193
      • Novo Nordisk Investigational Site
• Thailand
  • Bangkok, Thailand, 10400
    • Novo Nordisk Investigational Site
• Turkey
  • Ankara, Turkey, 06500
    • Novo Nordisk Investigational Site
  • Kayseri, Turkey, 38010
    • Novo Nordisk Investigational Site
  • Konya, Turkey, 42090
    • Novo Nordisk Investigational Site
• United Kingdom
  • Basingstoke, United Kingdom, RG24 9NA
    • Novo Nordisk Investigational Site
  • Cardiff, United Kingdom, CF14 4XW
    • Novo Nordisk Investigational Site
  • London, United Kingdom, NW3 2QG
    • Novo Nordisk Investigational Site
  • London, United Kingdom, SE1 7EH
    • Novo Nordisk Investigational Site
  • Manchester, United Kingdom, M13 9WL
    • Novo Nordisk Investigational Site
  • Oxford, United Kingdom, OX3 7LJ
    • Novo Nordisk Investigational Site
• United States
  • California
    • Los Angeles, California, United States, 90027-6016
      • Novo Nordisk Investigational Site
  • Florida
    • Jacksonville, Florida, United States, 32207
      • Novo Nordisk Investigational Site
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Novo Nordisk Investigational Site
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Novo Nordisk Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Novo Nordisk Investigational Site
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Novo Nordisk Investigational Site
  • Nebraska
    • Omaha, Nebraska, United States, 68198-5456
      • Novo Nordisk Investigational Site
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • Novo Nordisk Investigational Site
  • New York
    • New York, New York, United States, 10029
      • Novo Nordisk Investigational Site
    • Syracuse, New York, United States, 13210
      • Novo Nordisk Investigational Site
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Novo Nordisk Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • Novo Nordisk Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 13 years to 70 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Prophylaxis, high dose (trial duration 52 weeks)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience; Other Names: NNC-0156-0000-0009; Drug: nonacog beta pegol; Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, low dose (trial duration 52 weeks)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience; Other Names: NNC-0156-0000-0009; Drug: nonacog beta pegol; Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode; Other Names: NNC-0156-0000-0009
Experimental: On-demand (trial duration 28 weeks)	Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) once weekly. Patients will receive instruction on how to treat any bleeding episode they may experience; Other Names: NNC-0156-0000-0009; Drug: nonacog beta pegol; Patients will treat themselves with either a low or a high dose dependent on the severity of the bleeding episode; Other Names: NNC-0156-0000-0009

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	52 weeks after treatment start for patients on prophylaxis
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.	28 weeks after treatment start on on-demand treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	52 weeks after treatment start for patients on prophylaxis
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.	28 weeks after treatment start on on-demand treatment
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).	52 weeks after treatment start for patients on prophylaxis
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.	52 weeks after treatment start for patients on prophylaxis
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).	at 56 weeks ±2 weeks for patients on prophylaxis
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).	at 32 weeks ±2 weeks for patients on on-demand treatment
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).	at 56 weeks ±2 weeks for patients on prophylaxis
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).	at 32 weeks ±2 weeks for patients on on-demand treatment
Host Cell Proteins (HCP) Antibodies	Subjects who were positive for anti-Host Cell Protein (HCP) antibodies.	52 weeks after treatment start for patients on prophylaxis
Host Cell Proteins (HCP) Antibodies	Subjects who were positive for anti-HCP antibodies.	28 weeks after treatment start on on-demand treatment

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• 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.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): April 27, 2011
• Primary Completion (Actual): March 31, 2013
• Study Completion (Actual): March 31, 2013

Study Registration Dates

• First Submitted: April 8, 2011
• First Submitted That Met QC Criteria: April 8, 2011
• First Posted (Estimate): April 11, 2011

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: June 27, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; 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; Hemorrhage
• Other Study ID Numbers: NN7999-3747; 2010-023069-24 (EudraCT Number); U1111-1119-6415 (Other Identifier: WHO); JapicCTI-111644 (Other Identifier: Japic)