A Research Study on How Well Concizumab Works for You if You Have Haemophilia A or B With or Without Inhibitors

Study Overview
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Brief Summary
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This study will test how well a new medicine called concizumab works for participants who have haemophilia A or B with or without inhibitors. The purpose is to show that concizumab can prevent bleeds and is safe to use. Participants will have to inject the study medicine every day under the skin with a pen-injector. The study will last for at least 2 years and up to about 4 years. The length of time the participant will be in the study depends on if the study medicine will be available for purchase in their country.

Official Title
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Open-label Study Investigating Efficacy, Safety and Pharmacokinetics of Concizumab Prophylaxis in Children Below 12 Years With Haemophilia A or B With or Without Inhibitors

Conditions
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Haemophilia A and B With and Without Inhibitors

Intervention / Treatment
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* Drug: Concizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent/assent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study. Diagnosis of congenital severe haemophilia A (FVIII below 1%) or moderate/severe congenital haemophilia B (FIX (coagulation factor IX) below or equal to 2%), or congenital haemophilia with inhibitors. For arm 1 only: Male aged below 12 years of age at the time of signing informed consent. For arm 1 only: Patients with inhibitors (haemophilia A with inhibitors or haemophilia B with inhibitors) Patients with HAwI (haemophilia A with inhibitors) with historical medical records of a total of at least 26 weeks of on-demand treatment (On-demand or PPX treatment qualifying for this study is understood as patient-treatment solely for bleeds with intravenous coagulation factor-containing products) within the last 52 weeks prior to enrolment (For patients below 1 year of age that have been diagnosed with haemophilia <1 year prior to enrolment, historical medical records from time of diagnosis will suffice as long as medical records of a total of at least 26 weeks of relevant treatment is available). Patients with HBwI (haemophilia B with inhibitors) with historical medical records of a total of at least 26 weeks of on-demand treatment (On-demand or PPX treatment qualifying for this study is understood as patient-treatment solely for bleeds with intravenous coagulation factor-containing products) within the last 52 weeks prior to enrolment (For patients below 1 year of age that have been diagnosed with haemophilia <1 year prior to enrolment, historical medical records from time of diagnosis will suffice as long as medical records of a total of at least 26 weeks of relevant treatment is available). Patients with HBwI regardless of the regimen and duration of previous haemophilia treatment (On-demand or PPX treatment qualifying for this study is understood as patient-treatment solely for bleeds with intravenous coagulation factor-containing products) For arm 1 only: Patients without inhibitors (haemophilia A or haemophilia B) Patients with historical medical records of at least 52 weeks of on-demand treatment (On-demand or PPX treatment qualifying for this study is understood as patient-treatment solely for bleeds with intravenous coagulation factor-containing products; Surgery related PPX or short-term PPX (e.g., in relation to a severe bleed) is not allowed) during the last year prior to enrolment and with at least 3 documented treated bleeds (For participants less than (<) 2 years of age there is no limitation for number of documented treated bleeds in the medical history) during this period Patients with historical medical records of a total of at least 26 weeks of PPX (prophylaxis) treatment (On-demand or PPX treatment qualifying for this study is understood as patient-treatment solely for bleeds with intravenous coagulation factor-containing products) within the last 52 weeks prior to enrolment (For patients below 1 year of age that have been diagnosed with haemophilia <1 year prior to enrolment, historical medical records from time of diagnosis will suffice as long as medical records of a total of at least 26 weeks of relevant treatment is available) For arm 2 only: Male patients (regardless of age) previously treated with concizumab via compassionate use. Exclusion Criteria: Known or suspected hypersensitivity to study intervention or related products. Known inherited or acquired coagulation disorder other than congenital haemophilia. Ongoing or planned Immune Tolerance Induction treatment. History of thromboembolic disease (aIncludes arterial and venous thrombosis including myocardial infarction, pulmonary embolism, cerebral infarction/thrombosis, deep vein thrombosis, other clinically significant thromboembolic events and peripheral artery occlusion.). Current clinical signs of or treatment for thromboembolic disease. Patients who in the judgement of the investigator are considered at high risk of thromboembolic events (Thromboembolic risk factors could include, but are not limited to, hypercholesterolemia, diabetes mellitus, hypertension, obesity, smoking, family history of thromboembolic events, arteriosclerosis, other conditions associated with increased risk of thromboembolic events).
Sexes Eligible for Study
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All

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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Concizumab-naïve patients<br>Concizumab-naïve participants below 12 years of age at the time of consent/assent | Drug: Concizumab<br>* Participants in Arm 1 will be assigned to concizumab prophylaxis starting with a loading dose on treatment day 0 followed by daily injections of an individual maintenance dose. Participants in Arm 2 will be assigned to concizumab prophylaxis with daily injections of an individual maintenance dose.<br>|
| Experimental: Patients coming from compassionate use<br>Patients previously treated with concizumab via compassionate use, either on an individual patient basis or through the concizumab compassionate use programme NN7415-4807 | Drug: Concizumab<br>* Participants in Arm 1 will be assigned to concizumab prophylaxis starting with a loading dose on treatment day 0 followed by daily injections of an individual maintenance dose. Participants in Arm 2 will be assigned to concizumab prophylaxis with daily injections of an individual maintenance dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: Number of treated spontaneous and traumatic bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients treated on demand during at least the last 52 weeks prior enrolment: Number of treated spontaneous and traumatic bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: Number of all bleeding episodes (spontaneous and traumatic) | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: Number of treated spontaneous bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: Number of treated joint bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For inhibitor patients with at least 26 weeks on-demand treatment during the last 52 weeks prior enrolment: Number of treated bleeding episodes in baseline target joints | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients treated on-demand during at least the last 52 weeks prior enrolment: Number of all bleeding episodes (spontaneous and traumatic) | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients treated on-demand during at least the last 52 weeks prior enrolment: Number of treated spontaneous bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients treated on-demand at least the last 52 weeks prior enrolment: Number of treated joint bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients treated on-demand at least the last 52 weeks prior enrolment: Number of treated bleeding episodes in baseline target joints | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: Number of treated spontaneous and traumatic bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: Number of all bleeding episodes (spontaneous and traumatic) | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: Number of treated spontaneous bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: Number of treated joint bleeding episodes | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| For non-inhibitor patients with at least 26 weeks PPX treatment during the last 52 weeks prior enrolment: Number of treated bleeding episodes in baseline target joints | Count of episode(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Concizumab-naïve pateints - Number of treatment emergent adverse events, reported both separately for inhibitor and non-inhibitor patients and combined | Count of event(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of thromboembolic events, reported both separately for inhibitor and non-inhibitor patients and combined | Count of event(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of hypersensitivity type reactions, reported both separately for inhibitor and non-inhibitor patients and combined | Count of event(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of injection site reactions, reported both separately for inhibitor and non-inhibitor patients and combined | Count of event(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of patients who develop antibodies to concizumab - yes/no, reported both separately for inhibitor and non-inhibitor patients and combined | Count of patient(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Number of treatment emergent adverse events, reported both separately for inhibitor and non-inhibitor patients and combined | Count of event(s) | From start of treatment (week 0) up until the primary analysis cut-off (at least 32 weeks) | 
| Concizumab plasma concentrations prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined | Measured in ng/mL | Week 32 | 
| Peak thrombin generation prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined | Measured in nM | Week 32 | 
| Free TFPI concentration prior to dosing, reported both separately for inhibitor and non-inhibitor patients and combined | Measured in ng/mL | Week 32 | 
| Pre-dose (trough) concizumab plasma concentration (Ctrough), reported both separately for inhibitor and non-inhibitor patients and combined | Measured in ng/mL | Prior to the concizumab administration at week 20 | 
| Maximum concizumab plasma concentration (Cmax), reported both separately for inhibitor and non-inhibitor patients and combined | Measured in ng/mL | From 0 to 24 hours where 0 is the time of the concizumab dose at week 20 | 
| Area under the concizumab plasma concentration-time curve (AUC), reported both separately for inhibitor and non-inhibitor patients and combined | Measured in ng*hr/mL | From 0 to 24 hours where 0 is the time of the concizumab dose at week 20 |