Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin in Paediatric Subjects With Fibrinogen Deficiency

Study Overview
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Brief Summary
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This study will assess the efficacy of Octafibrin, a fibrinogen concentrate in in the on-demand treatment of spontaneous or traumatic bleeding episodes in paediatric patients less than 12 years of age.The planned study duration is up to 5 years. The study will be considered completed when a minimum of 6 subjects (i.e., at least 3 subjects aged between 0 and <6 years and 3 subjects aged between 6 and <12 years) have at least one documented bleeding episode and when in total a minimum of 2 surgical procedures have been performed. All patients will undergo a pharmacokinetic (PK) study after screening. This will have a duration of 14 days, after which a patient can be treated for a bleeding episode or planned surgical procedure when they occur.

Official Title
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Prospective, Open-label, Uncontrolled, Phase III Study to Assess the Efficacy, Safety and Pharmacokinetic of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery in Paediatric Subjects With Congenital Fibrinogen Deficiency

Conditions
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Congenital Fibrinogen Deficiency

Intervention / Treatment
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* Biological: Octafibrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged <12 years (at the start of treatment). Documented diagnosis of congenital fibrinogen deficiency, expected to require on-demand treatment for bleeding or surgical prophylaxis: Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrino-genaemia. Historical plasma fibrinogen activity of <50 mg/dL or levels below the limit of detection of the local assay method. Expected to have an acute bleeding episode (spontaneous or after trauma) or planning to undergo elective surgery. Informed consent signed by the subject's legal guardian. Exclusion Criteria: Life expectancy <6 months. Bleeding disorder other than congenital fibrinogen deficiency, including dysfi-brinogenaemia. Prophylactic treatment with a fibrinogen concentrate. Treatment with: Any fibrinogen concentrate or other fibrinogen-containing blood product within 2 weeks prior to start of treatment for the PK phase, a bleeding episode, or surgery. Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, war-farin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to start of the PK phase or treatment for the bleeding episode or surgery, or as a planned or expected medication during the time period from Day 1 until 24 hours (i.e., 1 day) after the last Octafibrin infusion. Presence or history of: Hypersensitivity to study medication. Deep vein thrombosis or pulmonary embolism within 1 year prior to start of treatment for the bleeding episode or surgery. Arterial thrombosis within 1 year prior to start of treatment for the bleeding episode or surgery Hypersensitivity to human plasma proteins. Oesophageal varicose bleeding. End-stage liver disease (i.e., Child-Pugh score B or C). Known positive HIV infection with a viral load >200 particles/μL or >400,000 copies/mL. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or any time in the past. Acute or chronic medical condition which may, in the opinion of investigator, affect the conduct of the study, including subjects receiving immune-modulating drugs (other than anti-retroviral chemotherapy), such as alpha-interferon, predni-sone (equivalent to >10 mg/day), or similar drugs, at study start. Treatment with IMP in another interventional clinical study currently or during the past 4 weeks.

Ages Eligible for Study
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Maximum Age: 11 Years

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Octafibrin<br>Plasma-derived fibrinogen concentrate | Biological: Octafibrin<br>* Plasma-derived Fibrinogen concentrate<br>* Other names: Fibrinogen concentrate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in the On-demand Treatment of the First Documented Bleeding Episode of Each Patient Based on a 4-point Haemostatic Efficacy Scale | The overall clinical assessment of the haemostatic efficacy of Octafibrin in treating the first documented bleeding episode (BE) of each patient. The first bleeding episode covered the time from the first Octafibrin infusion until 24 hours (i.e. 1 day) after the last infusion or the end of the treatment observation period, which ever came last. The investigator's overall clinical assessment of haemostatic efficacy for bleeding was based on a 4-point haemostatic efficacy scale (excellent, good, moderate or none). Excellent result was defined as immediate cessation of bleeding; 'Good' was eventual complete cessation of bleeding; 'Moderate' was incomplete cessation of bleeding and 'None' was no cessation of bleeding with alternative haemostatic intervention required. The IDMEAC conducted an independent adjudication of all haemostatic efficacy results and evaluated the investigator's assessments of the efficacy in the treatment of each BE. | First Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last | 
| Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in the On-demand Treatment of the First Documented Bleeding Episode of Each Patient Based on a 2-point Haemostatic Efficacy Scale | The overall clinical assessment of the haemostatic efficacy of Octafibrin in treating the first documented bleeding episode (BE) of each patient. The first bleeding episode covered the time from the first Octafibrin infusion until 24 hours (i.e. 1 day) after the last infusion or the end of the treatment observation period, which ever came last. The investigator's overall clinical assessment of haemostatic efficacy for bleeding was based on a 2-point haemostatic efficacy scale (success and failure). Efficacy rating of excellent or good on the four-point scale (above) indicated success and efficacy rating of moderate or none indicated failure. The IDMEAC conducted an independent adjudication of all haemostatic efficacy results and evaluated the investigator's assessments of the efficacy in the treatment of each BE. | From the first Octafibrin infusion until 24 hours (i.e. 1 day) after the last infusion or the end of the treatment observation period, which ever came last. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Single-dose Pharmacokinetics of Octafibrin: Area Under the Concentration-time Curve Normalised (AUCnorm) | AUCnorm (Area under the concentration-time curve normalized to the dose administered) was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Response - Incremental in Vivo Recovery (IVR) | IVR was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Between the pre-infusion and the 3-hour post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Terminal Elimination Half-life (t1/2) | t1/2 was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Maximum Plasma Concentration (Cmax) | Cmax was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Time to Reach Maximum Plasma Concentration (Tmax) | Tmax was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Mean Residence Time (MRT) | MRT was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Volume of Distribution (Vss) | Vss was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Single-dose Pharmacokinetics of Octafibrin: Clearance (Cl) | Cl was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 
| Change in Maximum Clot Firmness (MCF) for the First Bleeding Episode for Each Patients and for All Bleeding Episodes | MCF was measured using thromboelastometry (ROTEM). ROTEM is a method for the continuous measurement of clot formation and clot firmness. It utilises a mechanical detection system which is based on the ability of the blood or plasma clot to form a mechanical coupling over a distance of 1 mm. ROTEM was used to measure MCF as a surrogate efficacy marker for haemostatic efficacy before and after the first infusion of Octafibrin for treatment of the first bleeding episode and all bleeding episodes. The change in MCF was measured from baseline to 1 hour post-infusion of Octafibrin administration. | Before first infusion and 1 hour post-infusion of Octafibrin | 
| Change in the Fibrinogen Level for All Bleeding Episodes up to 1 Hour-post Infusion for the First Bleeding Episode and All Bleeding Episodes | Change in fibrinogen level was assessed using the Clauss fibrinogen assay for the first bleeding episode and all bleeding episodes. The change in fibrinogen level was assessed from Day 1 pre-infusion to 1 hour post-infusion of Octafibrin. | Pre-infusion and 1 hour post-infusion of Octafibrin | 
| Incremental in Vivo Recovery Following the First Infusion of Octafibrin Administration for the Treatment of the First Bleeding Episode and of All Bleeding Episodes | Incremental IVR calculated as the maximum increase in plasma fibrinogen (i.e. Clauss data) between the pre-infusion and the 3-hour post-infusion measurement, (expressed as absolute concentration in plasma [mg/dL]), divided by the exact dose of Octafibrin per body weight (expressed as mg/kg dosed). Incremental (response) IVR data for the firstBLEED and BLEED populations were calculated. | Pre-infusion and 3 hours post-infusion | 
| Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | The haemostatic efficacy of Octafibrin in the on-demand treatment of all bleeding episodes was based on a 4-point haemostatic efficacy scale ranging from excellent, good moderate and none. The efficacy assessment of each patients was assessed by the Investigator and the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). . | First Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last | 
| Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | The haemostatic efficacy of Octafibrin in the on-demand treatment of all bleeding episodes was based on a 2-point haemostatic efficacy scale ranging from success to failure. The efficacy assessment of each patients was assessed by the Investigator and the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). | First Octafibrin infusion for the treatment of a bleeding episode until 24 hours (i.e., 1 day) after the last infusion or the end of the treatment observation period, whichever comes last | 
| Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | The haemostatic efficacy of Octafibrin was assessed during surgery prophylaxis by the surgeon and the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC), on a 4-point scale ranging from excellent, good, moderate and none. Intra-operative blood loss lower or equal to the average expected blood loss was rates as 'Excellent'; intra-operative blood loss higher than average expected blood loss but lower or equal to maximal expected blood loss was rated as 'Good'; intra-operative blood loss was higher than expected blood loss was rated as 'Moderate' and haemostasis that was uncontrolled and necessitated a change in clotting factor replacement regimen was rated as 'None'. The surgical observation period started lasted from the first dose of Octafibrin to at least 3 post-operative days for minor and 7 post-operative days for major surgeries or until the day of the last post-operative infusion, whichever comes last. | First dose of Octafibrin prior to surgery until last day of post-operative infusion | 
| Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | The haemostatic efficacy of Octafibrin was assessed during surgery prophylaxis by the surgeon and the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC), on a 2-point scale ranging from success to failure. Efficacy rating of excellent or good from the 2-point efficacy scale indicated 'Success', and efficacy rating of moderate or none indicated 'Failure'. The surgical observation period started lasted from the first dose of Octafibrin to at least 3 post-operative days for minor and 7 post-operative days for major surgeries or until the day of the last post-operative infusion, whichever comes last. | First dose of Octafibrin prior to surgery until last day of post-operative infusion | 
| Patients With Elevated Values of Prothrombin Fragments 1+2 | Thrombogenicity was assessed by measuring the plasma levels of prothrombin fragment 1 (F1) and prothrombin fragment 2 (F2), before and after each Octafibrin infusion for the treatment of bleeding episodes during the study. This outcome measure examined the number of patients with elevated values of prothrombin fragments F1 + F2 that were outside of the reference range of 69 to 229 pmol/L, three hours post-infusion with Octafibrin. | 3 hours post-infusion of Octafibrin | 
| Safety Assessment: Immunogenicity Testing for Anti-fibrinogen Antibodies | The number of patients developing anti-fibrinogen antibodies were observed during the observation period using an experimental non-standard ELISA quantitative laboratory test. Immunogenicity testing for the presence of anti-fibrinogen antibodies before the first infusion of Octafibrin and on Day 30 after the treatment of each bleeding episode. | Start of the first Octafibrin infusion to the end of each 30-day observation and follow-up period for on-demand treatment | 
| Safety Assessment: Adverse Events | Adverse events, including thromboembolic complications and early signs of allergic or hypersensitivity reactions. | Start of the first Octafibrin infusion to the end of PK, end of 30-day observation and follow-up period for on-demand treatment, or the end of the surgical observation period |