Efficacy and Safety Study of Octafibrin for On-demand Treatment of Acute Bleeding and to Prevent Bleeding During and After Surgery

Study Overview
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Brief Summary
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The purpose of the study is to assess the efficacy and safety of Octafibrin for on-demand treatment of acute bleeding in subjects with congenital fibrinogen deficiency.

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

Conditions
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Congenital Fibrinogen Deficiency

Intervention / Treatment
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* Drug: Octafibrin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged ≥12 years (only 18 and above in Russia) Documented diagnosis of congenital fibrinogen deficiency, expected to require on-demand treatment for bleeding or surgical prophylaxis: Fibrinogen deficiency manifested as afibrinogenaemia or severe hypofibrinogenaemia. 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 or legal guardian. Exclusion Criteria: Life expectancy <6 months. Bleeding disorder other than congenital fibrinogen deficiency, including dysfibrinogenaemia. 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 bleeding episode or surgery. Any coagulation-active drug (i.e., non-steroidal anti-inflammatory drugs, warfarin, coumarin derivatives, platelet aggregation inhibitors) within 1 week prior to start of 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). Pregnant women within the first 20 weeks of gestation. Currently breast-feeding. 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, prednisone (equivalent to >10 mg/day), or similar drugs at study start. Subjects having evidence or a history (within the previous 12 months) of abuse of any licit or illicit drug substance. Participation in another interventional clinical study currently or during the past 4 weeks.

Ages Eligible for Study
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Minimum Age: 12 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> | Drug: Octafibrin<br> <br> |

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 Treating the First Documented Bleeding Episode of Each Patient. | The first bleeding episode covers the time period from the first Octafibrin infusion until 24 hours (i.e., 1 day) after the last infusion. The investigator's overall clinical assessment of haemostatic efficacy for bleeding was based on a 4 point haemostatic efficacy scale. The final efficacy assessment of each patient was adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC). | 24 hours after last infusion for each bleeding episode | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Clot Firmness (MCF) After Fibrinogen Infusion in Each Documented Bleeding Episode (BE), Measured in Frozen Plasma in a Central Laboratory. | MCF (mm) was determined using ROTEM and was used as a surrogate marker for haemostatic efficacy. 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. | Before first infusion and 1 hour after end of first and last infusion of each documented bleeding episode | 
| Fibrinogen Plasma Level | Fibrinogen plasma level was assessed using the Clauss fibrinogen assay | Before (pre-infusion), 1 hour and 3 hours after the end of each subsequent infusion as well as at the time of the overall clinical assessment of haemostatic efficacy (i.e., 24 hours after the last infusion of each documented bleeding episode) | 
| Response as Indicated by Incremental in Vivo Recovery (IVR) | Incremental IVR (response): calculated as the maximum increase in plasma fibrinogen (i.e., Clauss data) between pre-infusion and 1 and 3 hours post-infusion, divided by the exact dose of Octafibrin. | Pre-infusion and 1 and 3 hours post-infusion | 
| Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | The investigator's overall clinical assessment of haemostatic efficacy for bleeding will be based on a 4-point haemostatic efficacy scale. The final efficacy assessment of each patient will be adjudicated by the Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC) | 24 hours after last infusion for each bleeding episode | 
| Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | The efficacy of Octafibrin will be assessed at the end of surgery by the surgeon and post-operatively by the haematologist using two 4-point haemostatic efficacy scales. An overall efficacy assessment taking both the intra- and post-operative assessment into account will be adjudicated by the IDMEAC | First dose of Octafibrin administered prior to elective surgery to at least 3 post-operative days for minor and 7 post-operative days for major surgeries or last post-operative infusion, whichever comes last |