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

Study Overview
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Brief Summary
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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.

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

Conditions
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Congenital Bleeding Disorder, Haemophilia B

Intervention / Treatment
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* Drug: nonacog beta pegol


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NNC-0156-000-0009<br> | Drug: nonacog beta pegol<br>* A single dose of 40 U/kg will be administered intravenously, i.v. (into the vein) once weekly.<br>* Other names: NNC-0156-0000-0009;|

What is the study measuring?
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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 |