Congenital Bleeding Disorder, Congenital FXIII Deficiency
Conditions
Brief summary
The trial is conducted in Europe, North America and Asia. The aim of this trial is to evaluate catridecacog (recombinant factor XIII (rFXIII)) treatment in patients with inherited FXIII deficiency. It is expected that recombinant FXIII can be used for the prevention of bleeding episodes.
Interventions
DRUGcatridecacog
35 IU/kg body weight, i.v. administration, once every 4 weeks
Sponsors
Novo Nordisk A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of congenital FXIII A-subunit deficiency (confirmed by genotyping at screening visit) * Treatment with regular FXIII replacement therapy initiated at least 6 months prior to screening and one of the following : a documented history of at least one 1 treatment-requiring bleeding episode prior to initiation of regular replacement therapy or a documented family history of FXIII congenital deficiency (only for subjects on regular replacement therapy prior to screening) * Documented history of at least two 2 bleeding episodes requiring treatment with FXIII containing blood products within the last 12 months prior to screening (only for subjects receiving on-demand treatment prior to screening)
Exclusion criteria
* Known neutralizing antibodies (inhibitors) towards FXIII * Any known congenital or acquired coagulation disorder other than congenital FXIII deficiency * Documented history of at least 2 treatment-requiring bleeding episodes per year during previous regular replacement therapy with FXIII containing blood products (fresh frozen plasma (FFP), plasma-derived FXIII (pd FXIII) and cryoprecipitate) * Known or suspected allergy to trial product(s) or related products * Planned major surgery during the trial period. Catheter, ports and dental extractions do not count as surgeries and will not exclude the subject * Renal insufficiency defined as current dialysis therapy * Any history of confirmed venous or arterial thrombo-embolic events
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rate (Number Per Subject Year) of Bleeding Episodes Requiring Treatment With a FXIII Containing Product During the Treatment Period | For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16). | It represents the incidence of bleeding episodes requiring treatment with a FXIII-containing product. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects Having a Normal Clot Solubility One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16). | Blood samples for clot solubility drawn at each visit (1 hour before and after dose administration). A clot solubility assay was used to screen for FXIII deficiency. The assay is based on the ability of urea to dissolve fibrin clots that have not undergone FXIII-induced stabilization. Normal blood clots generally remain stable for 24 hours or more, while clots in which fibrin molecules have not been cross-linked are soluble within minutes. The outcome of the test is normal (FXIII present; a clot is observed in the test tube) or abnormal (FXIII absent or very low level; no clot in test tube). |
| Level of FXIII Activity One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16). | Subjects entered a 52-week treatment period of monthly (28±2 days) doses of 35 IU/kg rFXIII. Blood samples for analysis of FXIII activity were drawn at each visit; at dosing visits blood was drawn 1 hour after administration and before administration(corresponding to 28 days after the previous dose). All Dosing Visits are visits where a dose is given (i.e. Visit 2-15 except Visit 3). |
| Number of Subjects With rFXIII Antibody Development | For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16). | Subjects receiving rFXIII were monitored for the development of binding antibodies. Blood sampling was done before administration of trial product at all visits (Visits 1-16 and unscheduled visit) |
Countries
Austria, Canada, Finland, France, Germany, Israel, Italy, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Of a total of 29 initiated trial sites, 23 sites enrolled and dosed at least one patient. The country distribution was (number of actively recruiting sites per country in parenthesis): Austria (1), Canada (1), Finland (1), France (1), Germany (3), Israel (2), Italy (1), Spain (1), Switzerland (1), UK (3) and United States of America (8)
Pre-assignment details
After screening, eligible subjects entered a 4-week run-in period followed by a 52-week recombinant factor XIII (rFXIII) treatment period. Subjects who before entering the trial were receiving regular replacement therapy with a FXIII-containing product were to receive their last standard replacement dose just before the screening visit.
Participants by arm
| Arm | Count |
|---|---|
| rFXIII Subjects received 35 IU/kg rFXIII every 4th week (28±2 days) during a treatment period of 52 weeks. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice. Additional doses of rFXIII could therefore not be used to treat such breakthrough bleedings | 41 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | According to Protocol | 2 |
| Overall Study | Adverse Event | 1 |
| Overall Study | Development of antibodies | 3 |
| Overall Study | Unclassified | 2 |
Baseline characteristics
| Characteristic | rFXIII |
|---|---|
| Age, Continuous | 26.4 years STANDARD_DEVIATION 15.9 |
| Gender Female | 18 Participants |
| Gender Male | 23 Participants |
| Race/Ethnicity, Customized Asian | 5 participants |
| Race/Ethnicity, Customized Black or African American | 2 participants |
| Race/Ethnicity, Customized Other | 5 participants |
| Race/Ethnicity, Customized Unknown | 1 participants |
| Race/Ethnicity, Customized White | 28 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 25 / 41 |
| serious Total, serious adverse events | 6 / 41 |
Outcome results
Primary
Rate (Number Per Subject Year) of Bleeding Episodes Requiring Treatment With a FXIII Containing Product During the Treatment Period
It represents the incidence of bleeding episodes requiring treatment with a FXIII-containing product.
Time frame: For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16).
Population: Full analysis set - consisting of a total of 41 subjects who received at least one dose of trial product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| rFXIII | Rate (Number Per Subject Year) of Bleeding Episodes Requiring Treatment With a FXIII Containing Product During the Treatment Period | 0.138 bleeding episodes per subject per year |
95% CI: [0.0094, 0.2501]Poisson model (log-link)
Secondary
Level of FXIII Activity One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits
Subjects entered a 52-week treatment period of monthly (28±2 days) doses of 35 IU/kg rFXIII. Blood samples for analysis of FXIII activity were drawn at each visit; at dosing visits blood was drawn 1 hour after administration and before administration(corresponding to 28 days after the previous dose). All Dosing Visits are visits where a dose is given (i.e. Visit 2-15 except Visit 3).
Time frame: For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16).
Population: Full analysis set - consisting of a total of 41 subjects who received at least one dose of trial product. For All Dosing Visits, the participants analyzed (N) are the 'All Visit Subjects Count' i.e. the sum of subject counts across all dosing visits combined.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| rFXIII | Level of FXIII Activity One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | After 1 hour post-dosing (N=453) | 0.782 U/kg | Standard Deviation 0.342 |
| rFXIII | Level of FXIII Activity One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | After 28 days of treatment (N=459) | 0.189 U/kg | Standard Deviation 0.102 |
Secondary
Number of Subjects With rFXIII Antibody Development
Subjects receiving rFXIII were monitored for the development of binding antibodies. Blood sampling was done before administration of trial product at all visits (Visits 1-16 and unscheduled visit)
Time frame: For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16).
Population: Full analysis set - Subjects who received at least one dose of trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| rFXIII | Number of Subjects With rFXIII Antibody Development | 4 participants |
Secondary
Percentage of Subjects Having a Normal Clot Solubility One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits
Blood samples for clot solubility drawn at each visit (1 hour before and after dose administration). A clot solubility assay was used to screen for FXIII deficiency. The assay is based on the ability of urea to dissolve fibrin clots that have not undergone FXIII-induced stabilization. Normal blood clots generally remain stable for 24 hours or more, while clots in which fibrin molecules have not been cross-linked are soluble within minutes. The outcome of the test is normal (FXIII present; a clot is observed in the test tube) or abnormal (FXIII absent or very low level; no clot in test tube).
Time frame: For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16).
Population: Full analysis set - consisting of a total of 41 subjects who received at least one dose of trial product. For All Dosing Visits, the participants analyzed (N) are the 'All Visit Subjects Count' i.e. the sum of subject counts across all dosing visits combined.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| rFXIII | Percentage of Subjects Having a Normal Clot Solubility One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | After 1 hour post-dosing (N=444) | 98.2 percentage (%) of subjects |
| rFXIII | Percentage of Subjects Having a Normal Clot Solubility One Hour After rFXIII Administration and 28 Days After rFXIII Administration for All Dosing Visits | After 28 days of treatment (N=419) | 91.3 percentage (%) of subjects |