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

• ClinicalTrials.gov Identifier: NCT01467427
• Recruitment Status: Active, not recruiting
• First Posted: November 8, 2011
• Results First Posted: November 17, 2017
• Last Update Posted: April 19, 2023
• Sponsor: Novo Nordisk A/S
• Information provided by (Responsible Party): Novo Nordisk A/S

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Congenital Bleeding Disorder; Haemophilia B	Drug: nonacog beta pegol	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Safety, Efficacy and Pharmacokinetics of NNC-0156-0000-0009 in Previously Treated Children With Haemophilia B
• Actual Study Start Date: May 16, 2012
• Estimated Primary Completion Date: November 30, 2023
• Estimated Study Completion Date: November 30, 2023

Arms and Interventions

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 Name: NNC-0156-0000-0009

Outcome Measures

Primary Outcome Measures :

1. Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) Defined as Titre Above or Equal to 0.6 Bethesda Units (BU) [ Time Frame: From 0 to 52 weeks ]
   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.
2. Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) Defined as Titre Above or Equal to 0.6 Bethesda Units (BU) [ Time Frame: From week 52 until the last patient has completed the trial (no later than 30-Nov-2023) ]

Secondary Outcome Measures :

1. Number of Bleeding Episodes During Prophylaxis [ Time Frame: From 0 to 52 weeks ]
   The number of bleeding episodes per subject during routine prophylaxis was assessed using the individual annualised bleeding rates (bleeding episodes per subject per year).
2. Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor) [ Time Frame: From 0 to 52 weeks ]

   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:

   1. Excellent - abrupt pain relief and/or clear improvement in objective signs of bleeding within 8 hours after a single infusion.
   2. Good - noticeable pain relief and/or improvement in signs of bleeding within 8 hours after a single injection.
   3. Moderate - probable or slight beneficial effect within the first 8 hours after the first injection but requiring more than one infusion within 8 hours.
   4. 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.

3. Incremental Recovery at 30 Minutes (IR30min) [ Time Frame: Week 0 (30 minutes after first exposure) ]
   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.
4. Trough Level (Single-dose ) [ Time Frame: Week 0 (one week after first exposure) ]
   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).
5. Trough Level (Steady State) [ Time Frame: Week 4 to 52 weeks ]
   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.
6. Terminal Half-life (t1/2) [ Time Frame: Week 0 (30 minutes until one week after first exposure) ]
7. Number of Bleeding Episodes During Prophylaxis [ Time Frame: From week 52 until the last patient has completed the trial (no later than 30-Nov-2023) ]
8. Trough Level (Steady State) [ Time Frame: From week 52 until the patient has completed the trial (no later than 30-Nov-2023) ]
9. Haemostatic Effect of N9-GP in Treatment of Bleeding Episodes by 4-point Categorical Scale for Haemostatic Response (Excellent, Good, Moderate and Poor) [ Time Frame: From week 52 until the last patient has completed the trial (no later than 30-Nov-2023) ]
10. Number of Adverse Events [ Time Frame: From 0 to 52 weeks ]
    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.
11. Number of Serious Adverse Events (SAEs) [ Time Frame: From 0 to 52 weeks ]
    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.
12. Medical Events of Special Interest (MESI) [ Time Frame: From 0 to 52 weeks ]

    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.
13. Development of Host Cell Protein (HCP) Antibodies [ Time Frame: From 0 to 52 weeks ]
    Participants were examined for the development of antibodies against HCP. Number of participants who developed antibodies against HCP is presented.
14. FIX Consumption Described as Frequency of Dose/kg for Prophylaxis Use for the Treatment of Bleeding Episodes [ Time Frame: From 0 to 52 weeks ]
    Consumption of nonacog beta pegol for treatment of bleeding episodes per year per patient is presented.
15. FIX Consumption Described as Amount Consumed for the Treatment of Bleeding Episodes [ Time Frame: From 0 to 52 weeks ]
    Average dose of nonacog beta pegol for treatment of bleed from start to stop of bleed is presented.
16. Number of Doses of FIX Consumed for the Treatment of Bleeding Episodes [ Time Frame: From 0 to 52 weeks ]
    Number of doses of FIX consumed for the treatment of bleeding episodes is presented.
17. Area Under the Curve Activity Versus Time Profile From Time Zero to 168 Hours Post Dose (AUC(0-168)) [ Time Frame: 0-168 hours post-dosing at week 0 ]
    Area under the curve activity versus time profile from time zero to 168 hours post dose of nonacog beta pegol is presented.
18. Clearance (CL) [ Time Frame: 0-168 hours post-dosing at week 0 ]
    Clearance of nonacog beta pegol after single dose is presented.
19. Mean Residence Time (MRT) [ Time Frame: 0-168 hours post-dosing at week 0 ]
    Mean residence time (MRT) of nonacog beta pegol after single dose is presented.
20. Volume of Distribution at Steady State (Vss) [ Time Frame: 0-168 hours post-dosing at week 0 ]
    Volume of distribution at steady state (Vss) of nonacog beta pegol is presented.
21. FIX Activity at 30 Minutes (C30min) (Single Dose) [ Time Frame: 30 min post-dosing at week 0 ]
    FIX activity (international units per milliliter (IU/mL))at 30 minutes after single dose is presented.
22. FIX Activity at 30 Minutes (C30min) (Steady State) [ Time Frame: 30 min post-dosing from 4 to 52 weeks ]
    Mean FIX activity at 30 minutes post-dosing from 4 to 52 weeks (C30min) (steady state) is presented.
23. TNO-AZL Preschool Quality of Life (TAPQOL) [ Time Frame: Week 0, week 52 ]
    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.
24. Health Economic Impact of N9-GP Treatment Through Characterisation of General Hospitalisation [ Time Frame: From 0 to 52 weeks ]
    Health economic impact of N9-GP treatment is presented through number of general hospitalization days.
25. Health Economic Impact of N9-GP Treatment Through Characterisation of Intensive Care Hospitalisation [ Time Frame: From 0 to 52 weeks ]
    Health economic impact of N9-GP treatment is presented through number of intensive care hospitalization days.
26. Health Economic Impact of N9-GP Treatment Through Characterisation of Bleedings Caused Missing School or Studies [ Time Frame: From 0 to 52 weeks ]
    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.
27. Health Economic Impact of N9-GP Treatment Through Characterisation of Number of Days Bleedings Caused Using of Mobility Aids [ Time Frame: From 0 to 52 weeks ]
    Health economic impact of N9-GP treatment through number of days the patient used mobility aids (wheelchair and/or crutches) is presented.
28. Health Economic Impact of N9-GP Treatment Through Characterisation of Number of Days Bleedings Caused Parents to Miss Work [ Time Frame: From 0 to 52 weeks ]
    Health economic impact of N9-GP treatment through number of days bleedings caused parents to miss work is presented.

Eligibility Criteria

• Ages Eligible for Study: 0 Years to 12 Years (Child)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, District of Columbia

Novo Nordisk Investigational Site

Washington, District of Columbia, United States, 20010-2978

United States, Florida

Novo Nordisk Investigational Site

Miami, Florida, United States, 33136

United States, Iowa

Novo Nordisk Investigational Site

Iowa City, Iowa, United States, 52242

United States, Minnesota

Novo Nordisk Investigational Site

Minneapolis, Minnesota, United States, 55404

United States, Missouri

Novo Nordisk Investigational Site

Kansas City, Missouri, United States, 64108-4619

United States, Nebraska

Novo Nordisk Investigational Site

Omaha, Nebraska, United States, 68198-6828

United States, New Jersey

Novo Nordisk Investigational Site

New Brunswick, New Jersey, United States, 08901

United States, New York

Novo Nordisk Investigational Site

Brooklyn, New York, United States, 11220

Novo Nordisk Investigational Site

New York, New York, United States, 10029

United States, Ohio

Novo Nordisk Investigational Site

Cleveland, Ohio, United States, 44106

United States, Oklahoma

Novo Nordisk Investigational Site

Oklahoma City, Oklahoma, United States, 73104

United States, Pennsylvania

Novo Nordisk Investigational Site

Philadelphia, Pennsylvania, United States, 19104

United States, Tennessee

Novo Nordisk Investigational Site

Nashville, Tennessee, United States, 37232

United States, Texas

Novo Nordisk Investigational Site

Dallas, Texas, United States, 75235

Novo Nordisk Investigational Site

Houston, Texas, United States, 77030

Brazil

Novo Nordisk Investigational Site

Curitiba, Parana, Brazil, 80250-060

Novo Nordisk Investigational Site

Campinas, Sao Paulo, Brazil, 13081-970

Novo Nordisk Investigational Site

Rio de Janeiro, Brazil, 20211-030

Canada, Ontario

Novo Nordisk Investigational Site

Toronto, Ontario, Canada, M5G 1X8

Croatia

Novo Nordisk Investigational Site

Split, Croatia, 21 000

France

Novo Nordisk Investigational Site

Le Kremlin Bicetre, France, 94270

Novo Nordisk Investigational Site

Marseille, France, 13385

Novo Nordisk Investigational Site

Paris, France, 75015

Germany

Novo Nordisk Investigational Site

Duisburg, Germany, 47051

Novo Nordisk Investigational Site

Hannover, Germany, 30625

Italy

Novo Nordisk Investigational Site

Milano, MI, Italy, 20124

Japan

Novo Nordisk Investigational Site

Kanagawa, Japan, 216-8511

Novo Nordisk Investigational Site

Shizuoka, Japan, 420-8660

Novo Nordisk Investigational Site

Tokyo, Japan, 167-0035

Malaysia

Novo Nordisk Investigational Site

Kuala Lumpur, Malaysia, 50400

Taiwan

Novo Nordisk Investigational Site

Taipei, Taiwan, 100

United Kingdom

Novo Nordisk Investigational Site

Basingstoke, United Kingdom, RG24 9NA

Novo Nordisk Investigational Site

Birmingham, United Kingdom, B4 6NH

Novo Nordisk Investigational Site

Leicester, United Kingdom, LE1 5WW

Novo Nordisk Investigational Site

London, United Kingdom, SE1 7EH

Novo Nordisk Investigational Site

Oxford, United Kingdom, OX3 9DU

Sponsors and Collaborators

Novo Nordisk A/S

  Study Documents (Full-Text)

Documents provided by Novo Nordisk A/S:

Study Protocol and Statistical Analysis Plan  [PDF] June 27, 2018

More Information

Additional Information:

Clinical Trials at Novo Nordisk 

Publications of Results:

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.

Other 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)

• Responsible Party: Novo Nordisk A/S
• ClinicalTrials.gov Identifier: NCT01467427
• Other Study ID Numbers: NN7999-3774; 2011-000826-31 ( EudraCT Number ); U1111-1119-5013 ( Other Identifier: WHO ); JapicCTI- 121877 ( Registry Identifier: JAPIC )
• First Posted: November 8, 2011
• Results First Posted: November 17, 2017
• Last Update Posted: April 19, 2023
• Last Verified: April 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: According to the Novo Nordiskdisclosure commitment on novonordisk-trials.com

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Hemostatic Disorders; Hemophilia A; Hemophilia B; Blood Coagulation Disorders; Blood Coagulation Disorders, Inherited; Hematologic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Vascular Diseases; Cardiovascular Diseases