Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 in Previously Treated Children With Haemophilia B. (paradigm™5)

Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 in Previously Treated Children With Haemophilia B

This trial is conducted in Asia, Europe and North America. The aim of the trial is to evaluate safety, efficacy and pharmacokinetics (the exposure of the trial drug in the body) of NNC-0156-0000-0009 (nonacog beta pegol, N9-GP) in previously treated children with Haemophilia B.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Rio de Janeiro, Brazil, 20211-030
    • Hemorio-Fundarj
  • Parana
    • Curitiba, Parana, Brazil, 80250-060
      • Nucleo de Pesquisa Instituto Pele Pequeno Principe
  • Sao Paulo
    • Campinas, Sao Paulo, Brazil, 13081-970
      • Universidade Estadual de Campinas
• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• Croatia
  • Split, Croatia, 21 000
    • Clinical Hospital Centre Split, Firule, Paediatric Haem. Dpt
• France
  • Le Kremlin Bicetre, France, 94270
    • Hopital de Bicetre
  • Marseille, France, 13385
    • Hopital de la Timone
  • Paris, France, 75015
    • Hopital Necker
• Germany
  • Hannover, Germany, 30625
    • MHH-pädiatrische Hämatologie
• Italy
  • MI
    • Milano, MI, Italy, 20124
      • Istituto di Medicina Int. A. Bianchi Bonomi Univ. Milano
• Japan
  • Kanagawa, Japan, 216-8511
    • St. Marianna University School of Medicine Hospital_Pediatrics
  • Shizuoka, Japan, 420-8660
    • Shizuoka Children's Hospital, Hematology-Oncology
  • Tokyo, Japan, 167-0035
    • Ogikubo Hospital_Pediatries & Blood
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • National Blood Centre
• Taiwan
  • Taipei, Taiwan, 100
    • NTU Hospital - Children and Women Hospital
• United Kingdom
  • Basingstoke, United Kingdom, RG24 9NA
    • Centre for Haemophilia, Haemostasis and Thrombosis
  • Leicester, United Kingdom, LE1 5WW
    • Leicester Royal Infirmary
  • London, United Kingdom, SE1 7EH
    • St Thomas' Hospital
  • Oxford, United Kingdom, OX3 9DU
    • John Radcliffe Hospital
• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55404
      • Children's Hospitals and Clinics of Minnesota
  • New York
    • Brooklyn, New York, United States, 11220
      • Maimonides Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital Of Philadelphia_Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Hemostasis Thrombosis Clinic
  • Texas
    • Dallas, Texas, United States, 75235
      • Children's Medical Center_Dallas

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 12 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male patients with moderately severe or severe congenital haemophilia B with a Factor IX activity level below or equal to 2% according to medical records
• Age below or equal to 12 years (until patient turns 13 years, at time of inclusion)
• Body weight above or equal to 10 kg
• History of at least 50 exposure days (EDs) to other FIX products
• The patient and/or parent(s)/caregiver are capable of assessing a bleeding episode, keeping an electronic diary (eDiary), capable of conducting home treatment and otherwise able to follow trial procedures

Exclusion Criteria:

• Known history of FIX inhibitors
• Current FIX inhibitors above or equal to 0.6 Bethesda Units (BU)
• Congenital or acquired coagulation disorder other than haemophilia B
• Platelet count below 50,000/mcL at screening
• Alanine aminotransferase (ALT) above 3 times the upper limit of normal reference ranges at screening
• Creatinine level above or equal to 1.5 times above the upper normal limit of normal reference ranges at screening
• Human immunodeficiency virus (HIV) positive, defined by medical records, and with a CD4+ lymphocyte count below or equal to 200/mcL
• Immune modulating or chemotherapeutic medication (except single pulse treatment, inhaled and topical steroids)
• Previous arterial thrombotic events (myocardial infarction and intracranial thrombosis, as defined by medical records)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NNC-0156-000-0009	Drug: nonacog beta pegol; A single dose of 40 U/kg will be administered intravenously, i.v. (into the vein) once weekly.; 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 Coagulation Factor IX (FIX) Defined as Titre Above or Equal to 0.6 Bethesda Units (BU)	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.	From 0 to 52 weeks
Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) Defined as Titre Above or Equal to 0.6 Bethesda Units (BU)		From week 52 until the last patient has completed the trial (no later than 30-Nov-2023)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Bleeding Episodes During Prophylaxis	The number of bleeding episodes per subject during routine prophylaxis was assessed using the individual annualised bleeding rates (bleeding episodes per subject per year).	From 0 to 52 weeks
Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor)	Description of the haemostatic effect of nonacog beta pegol when used for treatment of bleeding episodes was measured and listed according to the four point scale for haemostatic response as below: Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single infusion.; 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 infusion within 8 hours.; Poor - no improvement, or worsening of symptoms within 8 hours after two injections. A success rate was calculated based on counting good or excellent as successes and poor and moderate as failures.	From 0 to 52 weeks
Incremental Recovery at 30 Minutes (IR30min)	The incremental recovery was calculated by dividing the baseline-subtracted factor IX activity (U/mL) measured in plasma 30 min after dosing by the dose injected at time 0 expressed as U/kg body weight.	Week 0 (30 minutes after first exposure)
Trough Level (Single-dose )	The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. Geometric mean of the lowest activity of factor IX recorded at week 0 (immediately before next dose was given).	Week 0 (one week after first exposure)
Trough Level (Steady State)	The mean pre-dose factor IX levels was measured with the one-stage clotting assay during the trial. The estimated mean of the lowest activity recorded immediately before next dose was given from week 4 to week 52. The analysis is based on a mixed model on the log-transformed plasma concentrations with subject as a random effect and the mean trough level is presented back-transformed to the natural scale.	Week 4 to 52 weeks
Terminal Half-life (t1/2)		Week 0 (30 minutes until one week after first exposure)
Number of Bleeding Episodes During Prophylaxis		From week 52 until the last patient has completed the trial (no later than 30-Nov-2023)
Trough Level (Steady State)		From week 52 until the patient has completed the trial (no later than 30-Nov-2023)
Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor)		From week 52 until the last patient has completed the trial (no later than 30-Nov-2023)
Number of Adverse Events	An adverse event (AE) was any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.	From 0 to 52 weeks
Number of Serious Adverse Events (SAEs)	A SAE was an experience that at any dose resulted in any of the following: death, a life-threatening experience a), In-patient hospitalisation or prolongation of existing hospitalisation b) a persistent or significant disability/incapacity c) a congenital anomaly/birth defect, Important medical events d) that did not result in death, were life-threatening a) or required hospitalization.	From 0 to 52 weeks
Medical Events of Special Interest (MESI)	The following events were defined as MESIs: -Medication errors concerning trial products, -Administration of wrong drug,; Wrong route of administration,; Administration of a high dose with the intention to cause harm, e.g. suicide attempt,; Administration of an accidental overdose: more than 20 % from the intended dose,; Inhibitor formation against factor IX (FIX),; Thromboembolic events,; Anaphylactic reaction.; Allergic reaction including, but not limited to, any acute immunoglobulin E (IgE) mediated reaction or delayed type hypersensitivity.	From 0 to 52 weeks
Development of Host Cell Protein (HCP) Antibodies	Participants were examined for the development of antibodies against HCP. Number of participants who developed antibodies against HCP is presented.	From 0 to 52 weeks
FIX Consumption Described as Frequency of Dose/kg for Prophylaxis Use for the Treatment of Bleeding Episodes	Consumption of nonacog beta pegol for treatment of bleeding episodes per year per patient is presented.	From 0 to 52 weeks
FIX Consumption Described as Amount Consumed for the Treatment of Bleeding Episodes	Average dose of nonacog beta pegol for treatment of bleed from start to stop of bleed is presented.	From 0 to 52 weeks
Number of Doses of FIX Consumed for the Treatment of Bleeding Episodes	Number of doses of FIX consumed for the treatment of bleeding episodes is presented.	From 0 to 52 weeks
Area Under the Curve Activity Versus Time Profile From Time Zero to 168 Hours Post Dose (AUC(0-168))	Area under the curve activity versus time profile from time zero to 168 hours post dose of nonacog beta pegol is presented.	0-168 hours post-dosing at week 0
Clearance (CL)	Clearance of nonacog beta pegol after single dose is presented.	0-168 hours post-dosing at week 0
Mean Residence Time (MRT)	Mean residence time (MRT) of nonacog beta pegol after single dose is presented.	0-168 hours post-dosing at week 0
Volume of Distribution at Steady State (Vss)	Volume of distribution at steady state (Vss) of nonacog beta pegol is presented.	0-168 hours post-dosing at week 0
FIX Activity at 30 Minutes (C30min) (Single Dose)	FIX activity (international units per milliliter (IU/mL))at 30 minutes after single dose is presented.	30 min post-dosing at week 0
FIX Activity at 30 Minutes (C30min) (Steady State)	Mean FIX activity at 30 minutes post-dosing from 4 to 52 weeks (C30min) (steady state) is presented.	30 min post-dosing from 4 to 52 weeks
TNO-AZL Preschool Quality of Life (TAPQOL)	The Dutch institute of Prevention and Health and the Leiden University Hospital (TNO-AZL) preschool quality of life clustered into 12 multi-item scales is used to assess the health-related quality of life, such as children's motor, communication, emotions, and body structure. Suitable for children from 6 months to 6 years old (TAPQOL). Parents fill in according to the child's condition. Higher score (range 0-100) represent better outcome. In this study, the TAPQOL was assessed for children of age 0-3 years.	Week 0, week 52
Health Economic Impact of N9-GP Treatment Through Characterisation of General Hospitalisation	Health economic impact of N9-GP treatment is presented through number of general hospitalization days.	From 0 to 52 weeks
Health Economic Impact of N9-GP Treatment Through Characterisation of Intensive Care Hospitalisation	Health economic impact of N9-GP treatment is presented through number of intensive care hospitalization days.	From 0 to 52 weeks
Health Economic Impact of N9-GP Treatment Through Characterisation of Bleedings Caused Missing School or Studies	Health economic impact of N9-GP treatment through number of days bleedings caused missing school or studies. Number of participants who missed school or studies for 0,1 and 2 days are presented.	From 0 to 52 weeks
Health Economic Impact of N9-GP Treatment Through Characterisation of Number of Days Bleedings Caused Using of Mobility Aids	Health economic impact of N9-GP treatment through number of days the patient used mobility aids (wheelchair and/or crutches) is presented.	From 0 to 52 weeks
Health Economic Impact of N9-GP Treatment Through Characterisation of Number of Days Bleedings Caused Parents to Miss Work	Health economic impact of N9-GP treatment through number of days bleedings caused parents to miss work is presented.	From 0 to 52 weeks

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S

Publications and helpful links

General Publications

• Safety, efficacy and pharmacokinetics of nonacog beta pegol (N9-GP) in prophylaxis and treatment of bleeding episodes in previously treated pediatric hemophilia B patients. Carcao M, Zak M, Abdul Karim F, Hanabusa H, Kearney S, Lu M-Y, Persson P, Rangarajan S, Santagostino E. Presented 06-Dec-2014 at the American Society of Hematology - 56th Annual Meeting - held in San Francisco, CA, US (poster #1513)
• Carcao M, Zak M, Abdul Karim F, Hanabusa H, Kearney S, Lu MY, Persson P, Rangarajan S, Santagostino E. Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial. J Thromb Haemost. 2016 Aug;14(8):1521-9. doi: 10.1111/jth.13360. Epub 2016 Jun 22.
• Carcao M, Kearney S, Lu MY, Taki M, Rubens D, Shen C, Santagostino E. Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B. Thromb Haemost. 2020 May;120(5):737-746. doi: 10.1055/s-0040-1709521. Epub 2020 May 5.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): May 16, 2012
• Primary Completion (Actual): November 17, 2023
• Study Completion (Actual): November 17, 2023

Study Registration Dates

• First Submitted: October 31, 2011
• First Submitted That Met QC Criteria: November 4, 2011
• First Posted (Estimated): November 8, 2011

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

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: NN7999-3774; 2011-000826-31 (EudraCT Number); U1111-1119-5013 (Other Identifier: WHO); JapicCTI- 121877 (Registry Identifier: JAPIC)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: According to the Novo Nordiskdisclosure commitment on novonordisk-trials.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No