Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Previously Untreated Patients With Haemophilia B (paradigm™6)

An Open-label Single-arm Multicentre Non-controlled Phase 3 a Trial Investigating Safety and Efficacy of Nonacog Beta Pegol (N9-GP) in Prophylaxis and Treatment of Bleeding Episodes in Previously Untreated Patients With Haemophilia B (FIX Activity Below or Equal to 2 Percent)

This trial is conducted globally. The aim of the trial is to investigate the safety and efficacy of nonacog beta pegol (N9-GP) in previously untreated patients with Haemophilia B.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 54
• Phase: Phase 3

Contacts and Locations

Study Locations

• Algeria
  • Algiers, Algeria, 16000
    • Beni Messous Hospital Issaad Hassani
  • Setif, Algeria, 19000
    • University Hospital Saadna Abdenour of Setif
• Argentina
  • Caba, Argentina, C1245AAM
    • Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan
  • Cordoba, Argentina, X5000FAL
    • Sanatorio Mayo Privado S.A
• Australia
  • Victoria
    • Parkville, Victoria, Australia, 3052
      • Royal Children's Hospital
• Austria
  • Graz, Austria, 8036
    • Med. Univ. Graz -Klinische Abteilung f. Allgemeine Pädiatrie
  • Innsbruck, Austria, 6020
    • Universitätsklinik Kinder-Jugendheilkunde
  • Klagenfurt, Austria, 9020
    • Klinikum Klagenfurt am Wörthersee (LKH Klagenfurt)
  • Linz, Austria, 4020
    • Landes-Frauen und Kinderklinik Linz
  • Salzburg, Austria, A 5020
    • LKH Salzburg- Univ. Klinik f. Kinder- und Jugendheilkunde
  • St. Poelten, Austria, A 3100
    • Ordination Prof. Zwiauer
  • Wien, Austria, A 1090
    • Universitätsklinik für Kinder- und Jugendheilkunde
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8N 3Z5
      • Hamltn Hth Sci/McMstr Child Hosp
• France
  • Clermont Ferrand, France, 63003
    • CHU Estaing
  • Kremlin-Bicêtre, France, 94270
    • Hopital de Bicetre
  • Nantes Cedex 1, France, 44093
    • Centre régional de traitement de l'Hémophilie
• Israel
  • Tel-Hashomer, Israel, 52621
    • Sheba MC The Israeli National Hemophilia Center
• Japan
  • Saitama, Japan, 330-8777
    • Saitama Children's Med Centre_Hematology-Oncology
• Malaysia
  • Georgetown, Penang, Malaysia, 10450
    • Hospital Pulau Pinang_Georgetown, Penang
  • Klang, Selangor, Malaysia, 41200
    • Hospital Tengku Ampuan Rahimah
  • Kuala Lumpur, Malaysia, 50400
    • National Blood Centre
  • Pahang
    • Kuantan, Pahang, Malaysia, 25100
      • Hospital Tengku Ampuan Afzan
• Spain
  • Esplugues Llobregat, Spain, 08950
    • Hospital Sant Joan de Déu
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Valencia, Spain, 46026
    • Hospital La Fe - Endocrinología y Nutrición
• Taiwan
  • Changhua, Taiwan, 500
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan, 807
    • Kaohsiung Medical University Chung-Ho Memorial Hospital_Kaohsiung
  • Taichung, Taiwan, 40447
    • China Medical University Hospital - Children Building
  • Taipei, Taiwan, 100
    • NTU Hospital - Children and Women Hospital
• Thailand
  • Bangkok, Thailand, 10400
    • Ramathibodi Hospital_Bangkok
  • Chiang Mai, Thailand, 50200
    • Hematology and Oncology, Dept.of Pediatrics, CMU
• United Kingdom
  • Birmingham, United Kingdom, B4 6NH
    • Birmingham Children's Hospital
  • 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
  • California
    • Los Angeles, California, United States, 90027
      • Children's Hosp-Los Angeles
  • Idaho
    • Boise, Idaho, United States, 83712
      • St. Luke's Mountain States Tumor Institute
  • Louisiana
    • New Orleans, Louisiana, United States, 70118-5720
      • Children's Hosp-New Orleans
  • Nebraska
    • Omaha, Nebraska, United States, 68198-6828
      • Univ of NE Med Center_Omaha
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
      • St.Jude Clin at Novant Hlth Hemby Cld Hosp
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Univ Hosp Cleveland Med Ctr
    • Dayton, Ohio, United States, 45404
      • Children's Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19134
      • St Christopher Hosp for Child
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Hemostasis Thrombosis Clinic
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Univ of Utah Primary Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial
• Male, age below 6 years at the time of signing informed consent
• Patients with the diagnosis of haemophilia B (FIX (coagulation factor IX) activity level below or equal to 2%) based on medical records or central laboratory results
• Previously untreated or exposed to FIX containing products less than or equal to 3 exposure days (5 previous exposures to blood components is acceptable)

Exclusion Criteria:

• Any history of FIX inhibitors (defined by medical records)
• Known or suspected hypersensitivity to trial product or related products
• Previous participation in this trial. Participation is defined as first dose administered of trial product
• Receipt of any investigational medicinal product within 30 days before screening
• Congenital or acquired coagulation disorder other than haemophilia B
• Any chronic disorder or severe disease which, in the opinion of the Investigator, might jeopardise the patient's safety or compliance with the protocol
• Patient's parent(s)/LAR(s) (legally acceptable representative) mental incapacity, unwillingness to cooperate, or a language barrier precluding adequate understanding and cooperation

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: 50 EDs (exposure days)	Drug: nonacog beta pegol; For intravenous (i.v.) injection. A single dose of 40 U/kg, unless the bleeding episode is severe in which case it should be treated with 80 U/kg.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Incidence of Inhibitory Antibodies Against Coagulation Factor IX (FIX) (50 Exposure Days)	Number of participants with incidence of inihibitory antibodies against FIX after 50 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.	When minimum 20 previously untreated patients (PUPs) have reached at least 50 exposure days (ED) (up to 156 weeks)
Number of Participants With Incidence of Inhibitory Antibodies Against FIX (100 ED)	Number of participants with incidence of inihibitory antibodies against FIX after 100 ED is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.	When minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
Number of Participants With Incidence of Inhibitory Antibodies Against FIX (At End of Trial)	Number of participants with incidence of inihibitory antibodies against FIX at end of trial is presented and defined as an inhibitory antibody titre greater than equal to 0.6 Bethesda unit (BU) at two consecutive tests performed at the central laboratory and also tested positive for nonacog beta pegol binding antibodies.	At end of trial (up to 434 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events	Number of adverse events after 50 ED, after 100 ED, and at end of trial is presented. An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Frequency of Adverse Events	Frequency of adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of adverse events was expressed as number of adverse events per participant years of exposure (total number of events /total time in trial). An adverse event was defined as any untoward medical occurrence in a participant who was administered a product, and which does not necessarily have a causal relationship with this treatment. All presented adverse events are treatment emergent adverse events, defined as an event that occured while the participant was on treatment in the period from first dosing with nonacog beta pegol to the end of trial/discontinuation of treatment.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Number of Serious Adverse Events	Number of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Frequency of Serious Adverse Events	Frequency of serious adverse events after 50 ED, after 100 ED, and at end of trial is presented. Frequency of serious adverse events was expressed as number of serious adverse events per participant years of exposure (total number of events /total time in trial). A serious adverse event was an experience that at any dose resulted in: death; life-threatening experience; in-patient hospitalisation or prolongation of existing hospitalisation; a persistent or significant disability/incapacity; congenital anomaly/birth defect; important medical events that may not result in death, be life-threatening/require hospitalisation could be considered a serious adverse event based upon appropriate medical judgement.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Number of Medical Events of Special Interest	Number of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. A medical event of special interest (MESI) was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event (serious or non-serious adverse event) that fulfils one or more of the following MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Frequency of Medical Events of Special Interest	Frequency of medical events of special interest after 50 ED, after 100 ED, and at end of trial is presented. It was expressed as number of MESI per participant years of exposure (total number of events/total time in trial). A MESI was an event that, in the evaluation of safety, has a special focus. A MESI was an adverse event that fulfils one or more of the MESI criteria: 1. Medication errors concerning the trial product; 2. Inhibitor formation against FIX; 3. Thromboembolic events; 4. Anaphylactic reaction; 5. Allergic reaction including, but not limited to, any acute immunoglobulin E mediated reaction of delayed-type hypersensitivity (clinical signs may include various types of skin rashes) that does not meet the definition of anaphylaxis; 6. CNS-related adverse events including, but not limited to, any learning and behavioral deficits; 7. Renal adverse events including new onset of renal disorder or renal impairment or acute and chronic renal failure.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Number of Breakthrough Bleeding Episodes During Prophylaxis (Annualised Bleeding Rate)	Number of breakthrough bleeding episodes during prophylaxis (annualised bleeding rate) after 50 ED, after 100 ED, and at end of trial is presented. Annualised bleeding rate is the number of bleeding episodes per year.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Haemostatic Effect of Nonacog Beta Pegol in Treatment of Bleeding Episodes by 4-point Haemostatic Response Scale ("Excellent", "Good", "Moderate" and "Poor")	Haemostatic effect of nonacog beta pegol in treatment of bleeding episodes by 4-point haemostatic response scale after 50 ED, after 100 ED, and at end of trial is presented. The haemostatic response after treatment of a bleed with nonacog beta pegol was evaluated on a 4-point scale as excellent, good, moderate or poor. Excellent: abrupt pain relief and/or clear improvement in objective signs of bleeding; Good: noticeable pain relief and/or improvement in signs of bleeding; Moderate: probable or slight beneficial effect after the first injection; Poor: no improvement or worsening of symptoms. If the haemostatic response was rated as excellent or good, the treatment of the bleed was considered a success. If the haemostatic response was rated as moderate or poor, the treatment was considered a failure.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Incremental Recovery at 30 Minutes (IR30min)	Incremental recovery 30 minutes post dosing (IR30min) after 50 ED, after 100 ED is presented. IR30min was defined as the rise in FIX activity per international units per kilogram (IU/kg) administered and was recorded 30 minutes after the end of nonacog beta pegol injection. It was calculated as the baseline adjusted FIX activity recorded 30 minutes after ended nonacog beta pegol injection divided by the administered dose (IU/kg body weight). It was recorded as international units per milliliter (IU/mL)/international units per kilogram (IU/kg).	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
FIX Activity at 30 Minutes (C30min)	FIX Activity 30 minutes post dosing (C30min) after 50 ED, after 100 ED is presented. The FIX activity was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks)
FIX Trough Levels	FIX trough levels after 50 ED, after 100 ED, and at end of trial is presented. FIX trough level was defined as the activity recorded immediately before nonacog beta pegol injection was given and was measured by one-stage clotting assay - a modified activated partial thromboplastin time (aPTT) assay. The analysis is based on a mixed model on the log-transformed plasma concentrations with participant as a random effect. The mean trough level is presented back-transformed to the natural scale.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Amount of Drug Administered to Treat a Bleeding Episode	Amount of nonacog beta pegol administered (average dose of nonacog beta pegol) to treat a bleeding episode after 50 ED, after 100 ED, and at end of trial is presented as international units per kilogram per bleed (IU/kg/bleed).	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)
Number of Injections Needed to Treat a Bleeding Episode	The mean number of injections needed to treat a bleeding episode is presented.	When minimum 20 PUPs have reached at least 50 ED (up to 156 weeks); when minimum 40 PUPs have reached at least 100 ED (up to 208 weeks); at end of trial (up to 434 weeks)

Collaborators and Investigators

• Sponsor: Novo Nordisk A/S
• Investigators: Study Director: Global Clinical Registry (GCR, 1452), Novo Nordisk A/S

Publications and helpful links

General Publications

• Chan AK, Alamelu J, Barnes C, Chuansumrit A, Garly ML, Meldgaard RM, Young G. Nonacog beta pegol (N9-GP) in hemophilia B: First report on safety and efficacy in previously untreated and minimally treated patients. Res Pract Thromb Haemost. 2020 Jul 29;4(7):1101-1113. doi: 10.1002/rth2.12412. eCollection 2020 Oct.

Helpful Links

• Clinical Trials at Novo Nordisk

Study record dates

Study Major Dates

• Study Start (Actual): July 2, 2014
• Primary Completion (Actual): October 27, 2022
• Study Completion (Actual): October 27, 2022

Study Registration Dates

• First Submitted: March 28, 2014
• First Submitted That Met QC Criteria: May 16, 2014
• First Posted (Estimated): May 19, 2014

Study Record Updates

• Last Update Posted (Actual): March 26, 2024
• Last Update Submitted That Met QC Criteria: March 25, 2024
• Last Verified: March 1, 2024

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: NN7999-3895; 2012-004867-38 (EudraCT Number); U1111-1135-9557 (Other Identifier: WHO); JapicCTI-142611 (Registry Identifier: JAPIC); NL53683.091.15 (Other Identifier: CCMO)