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

Congenital Bleeding Disorder Clinical Trial

— paradigm™6  

Official title:

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02141074
• Other study ID #: NN7999-3895
• Secondary ID: 2012-004867-38U1
• Status: Completed
• Phase: Phase 3
• Start date: July 2, 2014
• Est. completion date: October 27, 2022

Study information

• Verified date: March 2024
• Source: Novo Nordisk A/S
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: October 27, 2022
• Est. primary completion date: October 27, 2022
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 0 Years to 6 Years

Eligibility

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

Related Conditions & MeSH terms

• Blood Coagulation Disorders
• Congenital Bleeding Disorder
• Haemophilia B
• Hemophilia A
• Hemophilia B
• Hemorrhage
• Hemostatic Disorders

Intervention

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.

Locations

Country	Name	City	State
Algeria	Beni Messous Hospital Issaad Hassani	Algiers
Algeria	University Hospital Saadna Abdenour of Setif	Setif
Argentina	Hospital de Pediatría S.A.M.I.C. "Prof. Dr. Juan P. Garrahan	Caba
Argentina	Sanatorio Mayo Privado S.A	Cordoba
Australia	Royal Children's Hospital	Parkville	Victoria
Austria	Med. Univ. Graz -Klinische Abteilung f. Allgemeine Pädiatrie	Graz
Austria	Universitätsklinik Kinder-Jugendheilkunde	Innsbruck
Austria	Klinikum Klagenfurt am Wörthersee (LKH Klagenfurt)	Klagenfurt
Austria	Landes-Frauen und Kinderklinik Linz	Linz
Austria	LKH Salzburg- Univ. Klinik f. Kinder- und Jugendheilkunde	Salzburg
Austria	Ordination Prof. Zwiauer	St. Poelten
Austria	Universitätsklinik für Kinder- und Jugendheilkunde	Wien
Canada	Hamltn Hth Sci/McMstr Child Hosp	Hamilton	Ontario
France	CHU Estaing	Clermont Ferrand
France	Hopital de Bicetre	Kremlin-Bicêtre
France	Centre régional de traitement de l'Hémophilie	Nantes Cedex 1
Israel	Sheba MC The Israeli National Hemophilia Center	Tel-Hashomer
Japan	Saitama Children's Med Centre_Hematology-Oncology	Saitama
Malaysia	Hospital Pulau Pinang_Georgetown, Penang	Georgetown, Penang
Malaysia	Hospital Tengku Ampuan Rahimah	Klang, Selangor
Malaysia	National Blood Centre	Kuala Lumpur
Malaysia	Hospital Tengku Ampuan Afzan	Kuantan	Pahang
Spain	Hospital Sant Joan de Déu	Esplugues Llobregat
Spain	Hospital Universitario La Paz	Madrid
Spain	Hospital La Fe - Endocrinología y Nutrición	Valencia
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital_Kaohsiung	Kaohsiung
Taiwan	China Medical University Hospital - Children Building	Taichung
Taiwan	NTU Hospital - Children and Women Hospital	Taipei
Thailand	Ramathibodi Hospital_Bangkok	Bangkok
Thailand	Hematology and Oncology, Dept.of Pediatrics, CMU	Chiang Mai
United Kingdom	Birmingham Children's Hospital	Birmingham
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	St Thomas' Hospital	London
United Kingdom	John Radcliffe Hospital	Oxford
United States	St. Luke's Mountain States Tumor Institute	Boise	Idaho
United States	St.Jude Clin at Novant Hlth Hemby Cld Hosp	Charlotte	North Carolina
United States	Univ Hosp Cleveland Med Ctr	Cleveland	Ohio
United States	Children's Medical Center	Dayton	Ohio
United States	Children's Hosp-Los Angeles	Los Angeles	California
United States	Vanderbilt Hemostasis Thrombosis Clinic	Nashville	Tennessee
United States	Children's Hosp-New Orleans	New Orleans	Louisiana
United States	Univ of NE Med Center_Omaha	Omaha	Nebraska
United States	St Christopher Hosp for Child	Philadelphia	Pennsylvania
United States	Univ of Utah Primary Children's Hospital	Salt Lake City	Utah

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Algeria,  Argentina,  Australia,  Austria,  Canada,  France,  Israel,  Japan,  Malaysia,  Spain,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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)
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)

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