Congenital Fibrinogen Deficiency
Conditions
Brief summary
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.
Interventions
DRUGOctafibrin
Sponsors
Octapharma
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | 24 hours after last infusion for each bleeding episode | 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). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Clot Firmness (MCF) After Fibrinogen Infusion in Each Documented Bleeding Episode (BE), Measured in Frozen Plasma in a Central Laboratory. | Before first infusion and 1 hour after end of first and last infusion of each documented bleeding episode | 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. |
| Fibrinogen Plasma Level | 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) | Fibrinogen plasma level was assessed using the Clauss fibrinogen assay |
| Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | 24 hours after last infusion for each bleeding episode | 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) |
| Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | 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 | 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 |
| Response as Indicated by Incremental in Vivo Recovery (IVR) | Pre-infusion and 1 and 3 hours post-infusion | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies | Up to 30 days (start of the first Octafibrin infusion until the end of each 30-day observation and follow-up period for on-demand treatment or until the Last Post-Operative Day in surgeries) | Immunogenicity testing for the presence of anti-fibrinogen antibodies at Day 14 and Day 30 after the administration of Octafibrin for bleeding. An experimental non-standard ELISA was developed for this study for evaluating anti-fibrinogen antibodies. No specific test was performed to discern for neutralizing antibodies. The clinical implications of the assay results are not known. |
Countries
Bulgaria, India, Iran, Lebanon, Russia, Saudi Arabia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| SAFETY Population All patients who received at least one Octafibrin administration during the study. | 25 |
| Total | 25 |
Baseline characteristics
| Characteristic | SAFETY Population |
|---|---|
| Age, Categorical <=18 years | 6 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 19 Participants |
| Age, Continuous | 29.04 years STANDARD_DEVIATION 12.95 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Sex: Female, Male Female | 11 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 25 |
| other Total, other adverse events | 19 / 25 |
| serious Total, serious adverse events | 5 / 25 |
Outcome results
Primary
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).
Time frame: 24 hours after last infusion for each bleeding episode
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Excellent | 19 Participants |
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Good | 5 Participants |
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Moderate | 0 Participants |
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | None | 0 Participants |
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Missing | 0 Participants |
| Investigator Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Overall treatment success | 24 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Missing | 0 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Excellent | 23 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | None | 0 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Good | 1 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Overall treatment success | 24 Participants |
| IDMEAC Assessment | Overall Clinical Assessment of the Haemostatic Efficacy of Octafibrin in Treating the First Documented Bleeding Episode of Each Patient. | Moderate | 0 Participants |
Secondary
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)
Time frame: 24 hours after last infusion for each bleeding episode
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Excellent | 70 BEs |
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Good | 16 BEs |
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Moderate | 1 BEs |
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | None | 0 BEs |
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Missing | 2 BEs |
| Investigator Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Overall treatment success | 86 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Missing | 0 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Excellent | 81 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | None | 0 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Good | 7 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Overall treatment success | 88 BEs |
| IDMEAC Assessment | Efficacy of Octafibrin for All Bleeding Episodes Collected in the Study | Moderate | 1 BEs |
Secondary
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
Time frame: 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
| Arm | Measure | Group | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Overall treatment success | 12 Surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | None | 0 Surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Excellent | 11 Surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Moderate | 0 Surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Missing | 0 Surgeries |
| Investigator Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Good | 1 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Missing | 0 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Overall treatment success | 12 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Good | 1 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Excellent | 11 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Moderate | 0 Surgeries |
| IDMEAC Assessment | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | None | 0 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Excellent | 12 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Good | 0 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Missing | 0 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | None | 0 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Overall treatment success | 12 Surgeries |
| Day 1 Post-infusion 3 h | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Moderate | 0 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Overall treatment success | 12 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Excellent | 11 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Good | 1 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Moderate | 0 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | Missing | 0 Surgeries |
| 1 Day After Last Infusion | Efficacy of Octafibrin in Preventing Bleeding During and After Surgery | None | 0 Surgeries |
Secondary
Fibrinogen Plasma Level
Fibrinogen plasma level was assessed using the Clauss fibrinogen assay
Time frame: 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)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Fibrinogen Plasma Level | 0.13 mg/dL | Standard Deviation 1.17 |
| IDMEAC Assessment | Fibrinogen Plasma Level | 109.01 mg/dL | Standard Deviation 24.38 |
| Day 1 Post-infusion 3 h | Fibrinogen Plasma Level | 104.46 mg/dL | Standard Deviation 21.51 |
| 1 Day After Last Infusion | Fibrinogen Plasma Level | 70.77 mg/dL | Standard Deviation 20.59 |
Secondary
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.
Time frame: Before first infusion and 1 hour after end of first and last infusion of each documented bleeding episode
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Maximum Clot Firmness (MCF) After Fibrinogen Infusion in Each Documented Bleeding Episode (BE), Measured in Frozen Plasma in a Central Laboratory. | 5.79 mm | Standard Deviation 2.53 |
Secondary
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.
Time frame: Pre-infusion and 1 and 3 hours post-infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Investigator Assessment | Response as Indicated by Incremental in Vivo Recovery (IVR) | 1.82 mg/dL/(mg/kg) | Standard Deviation 0.42 |
Other Pre-specified
Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies
Immunogenicity testing for the presence of anti-fibrinogen antibodies at Day 14 and Day 30 after the administration of Octafibrin for bleeding. An experimental non-standard ELISA was developed for this study for evaluating anti-fibrinogen antibodies. No specific test was performed to discern for neutralizing antibodies. The clinical implications of the assay results are not known.
Time frame: Up to 30 days (start of the first Octafibrin infusion until the end of each 30-day observation and follow-up period for on-demand treatment or until the Last Post-Operative Day in surgeries)
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Investigator Assessment | Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies | Participants with Anti-fibrinogen Antibodies | 4 Participants |
| Investigator Assessment | Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies | Participants without Anti-fibrinogen Antibodies | 20 Participants |
| IDMEAC Assessment | Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies | Participants with Anti-fibrinogen Antibodies | 6 Participants |
| IDMEAC Assessment | Analysis of Safety: Immunogenicity Testing for Anti-fibrinogen Antibodies | Participants without Anti-fibrinogen Antibodies | 18 Participants |