Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B: An Extension to Trials NN7999-3747 and NN7999-3773 (paradigm™ 4)

Safety and Efficacy of NNC-0156-0000-0009 After Long-Term Exposure in Patients With Haemophilia B

This trial is conducted in Asia, Europe, Japan, North America and South Africa. The aim is to evaluate the safety and efficacy of nonacog beta pegol (NNC-0156-0000-0009) after long-term exposure in patients with haemophilia B.

This trial is an extension to trials NN7999-3747 (NCT01333111/paradigm™ 2) and NN7999-3773 (NCT01386528/paradigm™ 3).

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 71
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Novo Nordisk Investigational Site
• France
  • Bron Cedex, France, 69677
    • Novo Nordisk Investigational Site
  • Kremlin-Bicêtre, France, 94270
    • 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
• Greece
  • Athens, Greece, GR-11527
    • Novo Nordisk Investigational Site
• Italy
  • Firenze, Italy, 50134
    • Novo Nordisk Investigational Site
  • Milano, Italy, 20124
    • Novo Nordisk Investigational Site
• Japan
  • Kashihara-shi, Nara, Japan, 634 8522
    • Novo Nordisk Investigational Site
  • 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
• Romania
  • Timis
    • Timisoara, Timis, Romania, 300011
      • 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
• Spain
  • Madrid, Spain, 28046
    • Novo Nordisk Investigational Site
  • Valencia, Spain, 46026
    • Novo Nordisk Investigational Site
• Taiwan
  • Taipei, Taiwan, 100
    • 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
    • San Francisco, California, United States, 94143
      • Novo Nordisk Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • 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
  • 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:

• Previous participation in NN7999-3747 (NCT01333111) and/or NN7999-3773

Exclusion Criteria:

• Known history of FIX inhibitors based on existing medical records, laboratory report reviews and patient and LAR (legal acceptable representative) interviews
• Current FIX inhibitors above or equal to 0.6 BU (Bethesda Units)
• 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)
• Any disease (liver, kidney, inflammatory and mental disorders included) or condition which, according to the Investigator's (trial physician) judgement, could imply a potential hazard to the patient, interfere with trial participation, or interfere with trial outcome

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: On-demand	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; One single dose administered intravenously (into the vein). 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; Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) every second week. Patients will receive instruction on how to treat any bleeding episode they may experience.; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, high dose (once weekly)	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; One single dose administered intravenously (into the vein). 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; Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) every second week. Patients will receive instruction on how to treat any bleeding episode they may experience.; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, low dose (once weekly)	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; One single dose administered intravenously (into the vein). 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; Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) every second week. Patients will receive instruction on how to treat any bleeding episode they may experience.; Other Names: NNC-0156-0000-0009
Experimental: Prophylaxis, high dose (every second week)	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; One single dose administered intravenously (into the vein). 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; Drug: nonacog beta pegol; One single dose administered intravenously (into the vein) every second week. Patients will receive instruction on how to treat any bleeding episode they may experience.; 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 FIX Defined as Titre Above or Equal to 0.6 BU (Bethesda Units)	The primary endpoint was incidence of inhibitors against coagulation factor nine (FIX) defined as titre ≥0.6 Bethesda unit (BU). Number of subjects who developed inhibitors against FIX are reported.	From Day 1 up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Haemostatic Effect of Nonacog Beta Pegol When Used for Treatment of Bleeding Episodes, Assessed as Success/Failure Based on a Four-point Scale for Haemostatic Response (Excellent, Good, Moderate, Poor)	The haemostatic effect was evaluated by a four-point scale where an "excellent" or "good" outcome translated into a successful treatment, and a "moderate" or "poor" outcome was considered a treatment failure. The values mentioned below do not include bleeds with missing response.	From Day 1 up to 2 years
Number of Bleeding Episodes During Routine Prophylaxis	Annualized bleeding rate is the total number of bleeding episodes/total exposure time. It is analysed by a Poisson regression model with dose as a factor allowing for over-dispersion and using treatment duration as an offset. Median annualized bleeding rate is the median of individual annualized bleeding rates. Numbers are based on the treatment arm at the time of each bleed.	From Day 1 up to 2 years
FIX Trough Levels	During the trial, the pre-dose FIX levels was measured with the one-stage clotting assay. Measurements taken at least 5 days and no more than 10 days after last dose as well as at least 14 days after last bleeding episode were included in this analysis. The mean FIX trough levels were estimated based on the mixed effects model on the log-transformed plasma concentration with subject as a random effect. The mean FIX trough level was presented back-transformed to the natural scale.	From Day 1 up to 2 years
Incidence of Adverse Events (AEs)	AEs were summarized by frequency of events and frequency of patients with any event. Incidence of AEs was expressed as number of AEs per subject years of exposure (total number of events /total time in trial).	From Day 1 up to 2 years
Incidence of Serious Adverse Events (SAEs)	AEs were summarized by frequency of events and frequency of patients with any event. Incidence of serious AEs was expressed as number of serious AEs per subject years of exposure (total number of events /total time in trial).	From Day 1 up to 2 years

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Young G, Collins P, Tehranchi R, Chuansumrit A, Hanabusa H, Lentz SR, Mahlangu J, Mauser-Bunschoten E, Negrier C, Oldenburg J, Patiroglu T, Santagostino E, Zak M, Abdul Karim F. Safety and efficacy of nonacog beta pegol (N9-GP) for prophylaxis and treatment of bleeding episodes in previously-treated patients with hemophilia B: results from an extension trial. American Society of Hematology - 56th Annual Meeting (ASH) in San Francisco, CA, US
• Young G, Collins PW, Colberg T, Chuansumrit A, Hanabusa H, Lentz SR, Mahlangu J, Mauser-Bunschoten EP, Negrier C, Oldenburg J, Patiroglu T, Santagostino E, Tehranchi R, Zak M, Karim FA. Nonacog beta pegol (N9-GP) in haemophilia B: A multinational phase III safety and efficacy extension trial (paradigm4). Thromb Res. 2016 May;141:69-76. doi: 10.1016/j.thromres.2016.02.030. Epub 2016 Mar 2.
• Chowdary P, Kearney S, Regnault A, Hoxer CS, Yee DL. Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product. Haemophilia. 2016 Jul;22(4):e267-74. doi: 10.1111/hae.12995. Epub 2016 Jun 28.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): April 15, 2012
• Primary Completion (Actual): March 30, 2014
• Study Completion (Actual): March 30, 2014

Study Registration Dates

• First Submitted: June 30, 2011
• First Submitted That Met QC Criteria: July 15, 2011
• First Posted (Estimate): July 18, 2011

Study Record Updates

• Last Update Posted (Actual): May 9, 2018
• Last Update Submitted That Met QC Criteria: April 9, 2018
• Last Verified: April 1, 2018

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: NN7999-3775; 2010-023072-17 (EudraCT Number); U1111-1121-5408 (Other Identifier: WHO); JapicCTI-121812 (Registry Identifier: JAPIC)