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

Congenital Bleeding Disorder Clinical Trial

— paradigm™5  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01467427
• Other study ID #: NN7999-3774
• Secondary ID: 2011-000826-31U1
• Status: Completed
• Phase: Phase 3
• Start date: May 16, 2012
• Est. completion date: November 17, 2023

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 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: November 17, 2023
• Est. primary completion date: November 17, 2023
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 0 Years to 12 Years

Eligibility

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)

Related Conditions & MeSH terms

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

Intervention

Drug:
• nonacog beta pegol
A single dose of 40 U/kg will be administered intravenously, i.v. (into the vein) once weekly.

Locations

Country	Name	City	State
Brazil	Universidade Estadual de Campinas	Campinas	Sao Paulo
Brazil	Nucleo de Pesquisa Instituto Pele Pequeno Principe	Curitiba	Parana
Brazil	Hemorio-Fundarj	Rio de Janeiro
Canada	The Hospital for Sick Children	Toronto	Ontario
Croatia	Clinical Hospital Centre Split, Firule, Paediatric Haem. Dpt	Split
France	Hopital de Bicetre	Le Kremlin Bicetre
France	Hôpital de la Timone	Marseille
France	Hopital Necker	Paris
Germany	MHH-pädiatrische Hämatologie	Hannover
Italy	Istituto di Medicina Int. A. Bianchi Bonomi Univ. Milano	Milano	MI
Japan	St. Marianna University School of Medicine Hospital_Pediatrics	Kanagawa
Japan	Shizuoka Children's Hospital, Hematology-Oncology	Shizuoka
Japan	Ogikubo Hospital_Pediatries & Blood	Tokyo
Malaysia	National Blood Centre	Kuala Lumpur
Taiwan	NTU Hospital - Children and Women Hospital	Taipei
United Kingdom	Centre for Haemophilia, Haemostasis and Thrombosis	Basingstoke
United Kingdom	Leicester Royal Infirmary	Leicester
United Kingdom	St Thomas' Hospital	London
United Kingdom	John Radcliffe Hospital	Oxford
United States	Maimonides Medical Center	Brooklyn	New York
United States	Children's Medical Center_Dallas	Dallas	Texas
United States	Children's Hospitals And Clinics Of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt Hemostasis Thrombosis Clinic	Nashville	Tennessee
United States	Mount Sinai Medical Center	New York	New York
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Children's Hospital Of Philadelphia_Philadelphia	Philadelphia	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Novo Nordisk A/S

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Croatia,  France,  Germany,  Italy,  Japan,  Malaysia,  Taiwan,  United Kingdom, 

References & Publications (3)

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. — View Citation

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; — View Citation

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)

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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
Secondary	Terminal Half-life (t1/2)		Week 0 (30 minutes until one week after first exposure)
Secondary	Number of Bleeding Episodes During Prophylaxis		From week 52 until the last patient has completed the trial (no later than 30-Nov-2023)
Secondary	Trough Level (Steady State)		From week 52 until the patient has completed the trial (no later than 30-Nov-2023)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Clearance (CL)	Clearance of nonacog beta pegol after single dose is presented.	0-168 hours post-dosing at week 0
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   Clinical Trials at Novo Nordisk