Congenital Fibrinogen Deficiency
Conditions
Brief summary
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.
Interventions
BIOLOGICALOctafibrin
Plasma-derived Fibrinogen concentrate
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 11 Years
Healthy volunteers
No
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
1. Life expectancy \<6 months. 2. Bleeding disorder other than congenital fibrinogen deficiency, including dysfi-brinogenaemia. 3. Prophylactic treatment with a fibrinogen concentrate. 4. 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. 5. 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). 6. Known positive HIV infection with a viral load \>200 particles/μL or \>400,000 copies/mL. 7. Polytrauma 1 year prior to start of treatment for the bleeding episode or surgery. 8. Diagnosis or suspicion of a neutralizing anti-fibrinogen inhibitor currently or any time in the past. 9. 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. 10. Treatment with IMP in another interventional clinical study currently or during the past 4 weeks.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 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 | 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. |
| 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 | 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 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Single-dose Pharmacokinetics of Octafibrin: Terminal Elimination Half-life (t1/2) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | t1/2 was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Single-dose Pharmacokinetics of Octafibrin: Maximum Plasma Concentration (Cmax) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | Cmax was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Single-dose Pharmacokinetics of Octafibrin: Time to Reach Maximum Plasma Concentration (Tmax) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | Tmax was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Single-dose Pharmacokinetics of Octafibrin: Mean Residence Time (MRT) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | MRT was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Single-dose Pharmacokinetics of Octafibrin: Volume of Distribution (Vss) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | Vss was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Single-dose Pharmacokinetics of Octafibrin: Clearance (Cl) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | Cl was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
| Change in Maximum Clot Firmness (MCF) for the First Bleeding Episode for Each Patients and for All Bleeding Episodes | Before first infusion and 1 hour post-infusion of Octafibrin | 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. |
| Change in the Fibrinogen Level for All Bleeding Episodes up to 1 Hour-post Infusion for the First Bleeding Episode and All Bleeding Episodes | Pre-infusion and 1 hour post-infusion of Octafibrin | 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. |
| Single-dose Pharmacokinetics of Octafibrin: Area Under the Concentration-time Curve Normalised (AUCnorm) | Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion | 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. |
| Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | 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 | 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). . |
| Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | 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 | 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). |
| Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | First dose of Octafibrin prior to surgery until last day of post-operative infusion | 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. |
| Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | First dose of Octafibrin prior to surgery until last day of post-operative infusion | 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. |
| Patients With Elevated Values of Prothrombin Fragments 1+2 | 3 hours post-infusion of Octafibrin | 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. |
| Safety Assessment: Immunogenicity Testing for Anti-fibrinogen Antibodies | Start of the first Octafibrin infusion to the end of each 30-day observation and follow-up period for on-demand treatment | 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. |
| Safety Assessment: Adverse Events | 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 | Adverse events, including thromboembolic complications and early signs of allergic or hypersensitivity reactions. |
| Incremental in Vivo Recovery Following the First Infusion of Octafibrin Administration for the Treatment of the First Bleeding Episode and of All Bleeding Episodes | Pre-infusion and 3 hours post-infusion | 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. |
| Single-dose Pharmacokinetics of Octafibrin: Response - Incremental in Vivo Recovery (IVR) | Between the pre-infusion and the 3-hour post-infusion | IVR was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin. |
Countries
India, Iran, Lebanon
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Octafibrin The full analysis set (FAS) population defined according to the intention-to-treat principle, included the 14 patients who received at least one infusion of Octafibrin, and entered the study with a confirmed congenital fibrinogen deficiency. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Not treated during study period | 1 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Octafibrin |
|---|---|
| Age, Continuous | 6 years STANDARD_DEVIATION 2.57 |
| Body Mass Index (BMI) | 15.7 kg/m^2 STANDARD_DEVIATION 2.82 |
| Height | 111.3 centimetres (cm) STANDARD_DEVIATION 15.37 |
| Race/Ethnicity, Customized Race Asian | 4 Participants |
| Race/Ethnicity, Customized Race White | 10 Participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 19.8 kilograms (kg) STANDARD_DEVIATION 6.93 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 4 / 14 |
| serious Total, serious adverse events | 1 / 14 |
Outcome results
Primary
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.
Time frame: 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.
Population: The analysis was performed in the firstBLEED population which included patients in the full-analysis (FAS) population who had at least one bleeding episode treated with Octafibrin (n=8).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator Assessment | 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 | Success | 6 Participants |
| Investigator Assessment | 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 | Failure | 2 Participants |
| IDMEAC Assessment | 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 | Success | 8 Participants |
| IDMEAC Assessment | 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 | Failure | 0 Participants |
Primary
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.
Time frame: 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
Population: The analysis was performed in the firstBLEED population which included patients in the full-analysis (FAS) population who had at least one bleeding episode treated with Octafibrin (n=8).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator Assessment | 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 | Excellent | 5 Participants |
| Investigator Assessment | 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 | Good | 1 Participants |
| Investigator Assessment | 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 | Moderate | 1 Participants |
| Investigator Assessment | 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 | None | 1 Participants |
| IDMEAC Assessment | 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 | None | 0 Participants |
| IDMEAC Assessment | 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 | Excellent | 6 Participants |
| IDMEAC Assessment | 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 | Moderate | 0 Participants |
| IDMEAC Assessment | 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 | Good | 2 Participants |
Secondary
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.
Time frame: Before first infusion and 1 hour post-infusion of Octafibrin
Population: The analysis was performed in patients in the full-analysis set population that had at least one bleeding episode (BE) treated with Octafibrin (firstBLEED population: n=8), and all patients that had all documented BEs treated with Octafibrin (BLEED population: n=8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Change in Maximum Clot Firmness (MCF) for the First Bleeding Episode for Each Patients and for All Bleeding Episodes | 3.1 millimeter (mm) | Standard Deviation 1.96 |
| IDMEAC Assessment | Change in Maximum Clot Firmness (MCF) for the First Bleeding Episode for Each Patients and for All Bleeding Episodes | 3.3 millimeter (mm) | Standard Deviation 1.77 |
p-value: 0.0028ANOVA
p-value: 0.0002ANOVA
Secondary
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.
Time frame: Pre-infusion and 1 hour post-infusion of Octafibrin
Population: The analysis was performed in patients in the full-analysis set population that had at least one bleeding episode (BE) treated with Octafibrin (firstBLEED population: n=8), and all patients that had all documented BEs treated with Octafibrin (BLEED population: n=8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Change in the Fibrinogen Level for All Bleeding Episodes up to 1 Hour-post Infusion for the First Bleeding Episode and All Bleeding Episodes | 98.9 fibrinogen level (mg/dL) | Standard Deviation 13.56 |
| IDMEAC Assessment | Change in the Fibrinogen Level for All Bleeding Episodes up to 1 Hour-post Infusion for the First Bleeding Episode and All Bleeding Episodes | 98.1 fibrinogen level (mg/dL) | Standard Deviation 13.33 |
Secondary
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). .
Time frame: 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
Population: The analysis was performed in patients in the full-analysis set population that had all documented bleeding episodes treated with Octafibrin (BLEED population: n=8)
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Excellent | 7 Number of bleeding episodes |
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Moderate | 1 Number of bleeding episodes |
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Good | 1 Number of bleeding episodes |
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | None | 1 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Good | 2 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Excellent | 8 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | None | 0 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Four-point Haemostatic Efficacy Scale | Moderate | 0 Number of bleeding episodes |
Secondary
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).
Time frame: 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
Population: The analysis was performed in patients in the full-analysis set population that had all documented bleeding episodes treated with Octafibrin (BLEED population: n=8)
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | Success | 8 Number of bleeding episodes |
| Investigator Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | Failure | 2 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | Success | 10 Number of bleeding episodes |
| IDMEAC Assessment | Efficacy of Octafibrin in All Bleeding Episodes Based on a Two-point Haemostatic Efficacy Scale | Failure | 0 Number of bleeding episodes |
Secondary
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.
Time frame: First dose of Octafibrin prior to surgery until last day of post-operative infusion
Population: The analysis was performed in patients in the full-analysis set population with documented surgical interventions treated with at least one infusion of Octafibrin (n=3).
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Excellent | 3 Number of surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Good | 0 Number of surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Moderate | 0 Number of surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | None | 0 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | None | 0 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Excellent | 3 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Moderate | 0 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Four-point Haemostatic Efficacy Scale | Good | 0 Number of surgeries |
Secondary
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.
Time frame: First dose of Octafibrin prior to surgery until last day of post-operative infusion
Population: The analysis was performed in patients in the full-analysis set population with documented surgical interventions treated with at least one infusion of Octafibrin (n=3).
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | Success | 3 Number of surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | Failure | 0 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | Success | 3 Number of surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Surgical Prophylaxis Based on a Two-point Haemostatic Efficacy Scale | Failure | 0 Number of surgeries |
Secondary
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.
Time frame: Pre-infusion and 3 hours post-infusion
Population: The analysis was performed in patients in the full-analysis set population that had at least one bleeding episode (BE) treated with Octafibrin (firstBLEED population: n=8), and all patients that had all documented BEs treated with Octafibrin (BLEED population: n=8)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Incremental in Vivo Recovery Following the First Infusion of Octafibrin Administration for the Treatment of the First Bleeding Episode and of All Bleeding Episodes | 1.5 (mg/dL)/(mg/kg) | Standard Deviation 0.29 |
| IDMEAC Assessment | Incremental in Vivo Recovery Following the First Infusion of Octafibrin Administration for the Treatment of the First Bleeding Episode and of All Bleeding Episodes | 1.5 (mg/dL)/(mg/kg) | Standard Deviation 0.34 |
Secondary
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.
Time frame: 3 hours post-infusion of Octafibrin
Population: The analysis was performed in all patients in the safety population that met the study inclusion criteria and received at least one infusion of Octafibrin (n=14).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Investigator Assessment | Patients With Elevated Values of Prothrombin Fragments 1+2 | 3 Participants |
Secondary
Safety Assessment: Adverse Events
Adverse events, including thromboembolic complications and early signs of allergic or hypersensitivity reactions.
Time frame: 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
Population: The analysis was performed in all patients in the safety population that met the inclusion criteria and received at least one infusion of Octafibrin during the study (n=14)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Investigator Assessment | Safety Assessment: Adverse Events | 10 Number of adverse events |
Secondary
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.
Time frame: Start of the first Octafibrin infusion to the end of each 30-day observation and follow-up period for on-demand treatment
Population: The analysis was performed in all patients in the safety population that met the inclusion criteria and received at least one infusion of Octafibrin during the study (n=14)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Investigator Assessment | Safety Assessment: Immunogenicity Testing for Anti-fibrinogen Antibodies | 2 Participants |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Area Under the Concentration-time Curve Normalised (AUCnorm) | 1.419 h*kg*g/L/mg | Standard Deviation 0.4385 |
Secondary
Single-dose Pharmacokinetics of Octafibrin: Clearance (Cl)
Cl was assessed after a single intravenous infusion of 70 mg/kg body weight of Octafibrin.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Clearance (Cl) | 0.756 mL/h/kg | Standard Deviation 0.1872 |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Maximum Plasma Concentration (Cmax) | 1.559 g/L | Standard Deviation 0.3183 |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Mean Residence Time (MRT) | 114.332 hours | Standard Deviation 37.9732 |
Secondary
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.
Time frame: Between the pre-infusion and the 3-hour post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level (n=13)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Response - Incremental in Vivo Recovery (IVR) | 1.592 mg/dL/(mg/kg) | Standard Deviation 0.3224 |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Terminal Elimination Half-life (t1/2) | 84.356 hours | Standard Deviation 34.2658 |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level (n=13).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Time to Reach Maximum Plasma Concentration (Tmax) | 1.154 hours | Standard Deviation 0.5547 |
Secondary
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.
Time frame: Before first infusion, 1 hour, 3 hours, 1 day, 2 days, 4 days, 7 days, 10 days and 14 days post-infusion
Population: The analysis was performed in the pharmacokinetic (PK) population, which included all patients in the full-analysis (FAS) population who underwent PK assessment and had at least one valid post-baseline fibrinogen activity level.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Single-dose Pharmacokinetics of Octafibrin: Volume of Distribution (Vss) | 81.651 mL/kg | Standard Deviation 15.2735 |