Congenital Bleeding Disorder, Congenital FXIII Deficiency
Conditions
Brief summary
This trial is conducted in Europe and United States of America (USA). The aim of this clinical trial is to investigate the pharmacokinetics (at which rate the substance is distributed and eliminated from the body) and the safety profile of catridecacog (recombinant factor XIII (rFXIII)) in children with congenital FXIII A-subunit deficiency. Young children (1 to less than 6 years old) with congenital FXIII deficiency are evaluated.
Interventions
DRUGcatridecacog
Intravenous injection of a single dose of recombinant factor XIII, 35 IU/kg bodyweight
Sponsors
Novo Nordisk A/S
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 6 Years
Healthy volunteers
No
Inclusion criteria
* Signed Informed Consent by subject's parents or subject's legally acceptable representative before any trial related activities. Trial related activities are any procedures that would not have been performed during the normal management of the subject * Age 1 to less than 6 years old at the time of enrolment * Congenital FXIII subunit-A deficiency previously documented by genotyping or evaluated by genotyping through blood sampling at screening visit * Body weight at least 10 kg
Exclusion criteria
* Known antibodies to FXIII * Hereditary or acquired coagulation disorder other than FXIII A-subunit congenital deficiency * Platelet count (thrombocytes) of less than 50 × 10\^9/L (at screening visit) * Previous history of autoimmune disorder involving autoantibodies e.g., systemic lupus erythematosus * Previous history of arterial or venous thromboembolic events e.g., cerebrovascular accident or deep vein thrombosis * Known or suspected allergy to trial product or related products * Any surgical procedure in the 30 days prior to enrolment and any planned surgery during the trial period * Any disease or condition which, judged by the Investigator, could imply a potential hazard to the subject or interfere with the trial participation or trial outcome including renal and/or liver dysfunction
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration vs. Time Curve (AUC) | At pre-dose, 30 minutes, 24 hours, 7, 14, 21 and 30 days after dosing | A measure of the exposure. Blood samples for the PK assessment were drawn pre-dose and up to 30 days after dosing. The PK of FXIII in children was assessed after a single i.v. dose of rFXIII 35 IU/kg. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coagulation Related Parameters - Activated Partial Thromboplastin Time (aPTT, Seconds) | Day 0 and day 30 | — |
| Area Under the Concentration vs. Time Curve (AUC0-∞) | From day 0 to day 30 | A measure of exposure. |
| Maximum Plasma Concentration (Cmax) for FXIII | At pre-dose, 30 minutes, 24 hours, 7, 14, 21 and 30 days after dosing | Maximum plasma concentration of the drug reached. |
| Terminal Half-life (t½) | From day 0 to day 30 | Time point when half of the maximum plasma concentration is reached. |
| Mean Residence Time (MRT) | From day 0 to day 30 | The mean residence time (MRT) of a drug in the body and related functions are derived for drugs which are intravenously administered. |
| Total Plasma Clearance (CL) | From day 0 to day 30 | The total plasma clearance is a measure of the elimination of a drug from the body. Drugs are excreted primarily by the kidneys into the urine. Clearance is calculated as 'CL=Dose / AUC0-30 days'). |
| Volume of Distribution at Steady State (Vss) | At steady state | Volume of distribution at steady state (Vss) is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state. Steady state is achieved when all variables are constant in spite of ongoing processes. |
| Coagulation Related Parameters - Fibrinogen | Day 0 and at day 30 | — |
| Percentage of Subjects With One or More Serious Adverse Events (SAEs) | From day 0 to day 30 | — |
| Percentage of Subjects With Development of Anti-rFXIII Antibodies, Including Inhibitors (Neutralising Antibodies Against Factor XIII) | At screening and day 30 | — |
| Coagulation Related Parameters - Prothrombin Time (PT) (Seconds) | Day 0 and day 30 | — |
| Clot Solubility Test (Evaluated as Normal/Abnormal) | Day 0 and day 30 | 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). |
| Vital Signs - Pulse | Day 0 and day 30 | — |
| Vital Signs - Blood Pressure (Systolic and Diastolic) | Day 0 and day 30 | — |
| Physical Examination (Evaluated as Normal/Abnormal) | From day 0 to day 30 | — |
| Percentage of Subjects With One or More Adverse Events (AEs) Recorded | From day 0 to day 30 | — |
Countries
Israel, United Kingdom, United States
Participant flow
Recruitment details
The trial was conducted at five sites located in the UK (2 sites), Israel (1 site) and the US (2 sites).
Pre-assignment details
Between screening and treatment with trial drug the children were assessed for eligibility. If eligible, the children were treated with one single dose of FXIII. The trial was not randomised.
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Factor XIII One single dose of 35 IU/kg rFXIII was administered as an intravenous (i.v.) injection to each child. The trial included one screening visit, one treatment visit (including pharmacokinetics (PK) assessments up to 24 hours) and 4 follow-up visits (at 7, 14, 21 and 30 days after dosing). Blood samples for PK assessments were drawn pre-dose and up to 30 days after dosing. | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Recombinant Factor XIII |
|---|---|
| Age, Continuous | 2.67 years STANDARD_DEVIATION 1.03 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Gender Female | 3 Participants |
| Gender Male | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 1 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 | 0 Participants |
| Race (NIH/OMB) White | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Area Under the Concentration vs. Time Curve (AUC)
A measure of the exposure. Blood samples for the PK assessment were drawn pre-dose and up to 30 days after dosing. The PK of FXIII in children was assessed after a single i.v. dose of rFXIII 35 IU/kg.
Time frame: At pre-dose, 30 minutes, 24 hours, 7, 14, 21 and 30 days after dosing
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Area Under the Concentration vs. Time Curve (AUC) | 250.25 IU*h/mL | Standard Deviation 31.19 |
Secondary
Area Under the Concentration vs. Time Curve (AUC0-∞)
A measure of exposure.
Time frame: From day 0 to day 30
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Area Under the Concentration vs. Time Curve (AUC0-∞) | 403.18 IU*h/mL | Standard Deviation 92.2 |
Secondary
Clot Solubility Test (Evaluated as Normal/Abnormal)
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: Day 0 and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Normal (pre-dose) | 4 participants |
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Abnormal (pre-dose) | 1 participants |
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Not done (pre-dose) | 1 participants |
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Normal (post-dose) | 5 participants |
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Abnormal (post-dose) | 0 participants |
| Recombinant Factor XIII | Clot Solubility Test (Evaluated as Normal/Abnormal) | Not done (post-dose) | 1 participants |
Secondary
Coagulation Related Parameters - Activated Partial Thromboplastin Time (aPTT, Seconds)
Time frame: Day 0 and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Factor XIII | Coagulation Related Parameters - Activated Partial Thromboplastin Time (aPTT, Seconds) | Pre-dose | 33.8 Sec | Standard Deviation 9 |
| Recombinant Factor XIII | Coagulation Related Parameters - Activated Partial Thromboplastin Time (aPTT, Seconds) | Post-dose | 30.3 Sec | Standard Deviation 5.6 |
Secondary
Coagulation Related Parameters - Fibrinogen
Time frame: Day 0 and at day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Factor XIII | Coagulation Related Parameters - Fibrinogen | Pre-dose | 3.26 g/L | Standard Deviation 1.04 |
| Recombinant Factor XIII | Coagulation Related Parameters - Fibrinogen | Post-dose 30 days | 3.46 g/L | Standard Deviation 0.82 |
Secondary
Coagulation Related Parameters - Prothrombin Time (PT) (Seconds)
Time frame: Day 0 and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Factor XIII | Coagulation Related Parameters - Prothrombin Time (PT) (Seconds) | Pre-dose | 12.6 Sec | Standard Deviation 0.7 |
| Recombinant Factor XIII | Coagulation Related Parameters - Prothrombin Time (PT) (Seconds) | Post-dose | 12.1 Sec | Standard Deviation 2.3 |
Secondary
Maximum Plasma Concentration (Cmax) for FXIII
Maximum plasma concentration of the drug reached.
Time frame: At pre-dose, 30 minutes, 24 hours, 7, 14, 21 and 30 days after dosing
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Maximum Plasma Concentration (Cmax) for FXIII | 0.69 U/mL | Standard Deviation 0.14 |
Secondary
Mean Residence Time (MRT)
The mean residence time (MRT) of a drug in the body and related functions are derived for drugs which are intravenously administered.
Time frame: From day 0 to day 30
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Mean Residence Time (MRT) | 729.01 hours | Standard Deviation 265.98 |
Secondary
Percentage of Subjects With Development of Anti-rFXIII Antibodies, Including Inhibitors (Neutralising Antibodies Against Factor XIII)
Time frame: At screening and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recombinant Factor XIII | Percentage of Subjects With Development of Anti-rFXIII Antibodies, Including Inhibitors (Neutralising Antibodies Against Factor XIII) | At screening | 50 percentage of subjects |
| Recombinant Factor XIII | Percentage of Subjects With Development of Anti-rFXIII Antibodies, Including Inhibitors (Neutralising Antibodies Against Factor XIII) | Day 30 | 50 percentage of subjects |
Secondary
Percentage of Subjects With One or More Adverse Events (AEs) Recorded
Time frame: From day 0 to day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Factor XIII | Percentage of Subjects With One or More Adverse Events (AEs) Recorded | 33.3 percentage (%) of subjects |
Secondary
Percentage of Subjects With One or More Serious Adverse Events (SAEs)
Time frame: From day 0 to day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Factor XIII | Percentage of Subjects With One or More Serious Adverse Events (SAEs) | 0 percentage of subjects |
Secondary
Physical Examination (Evaluated as Normal/Abnormal)
Time frame: From day 0 to day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recombinant Factor XIII | Physical Examination (Evaluated as Normal/Abnormal) | Normal (pre-dose) | 6 participants |
| Recombinant Factor XIII | Physical Examination (Evaluated as Normal/Abnormal) | Abnormal (pre-dose) | 0 participants |
| Recombinant Factor XIII | Physical Examination (Evaluated as Normal/Abnormal) | Normal (post-dose) | 5 participants |
| Recombinant Factor XIII | Physical Examination (Evaluated as Normal/Abnormal) | Abnormal (post-dose) | 1 participants |
Secondary
Terminal Half-life (t½)
Time point when half of the maximum plasma concentration is reached.
Time frame: From day 0 to day 30
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Recombinant Factor XIII | Terminal Half-life (t½) | 378 hours |
Secondary
Total Plasma Clearance (CL)
The total plasma clearance is a measure of the elimination of a drug from the body. Drugs are excreted primarily by the kidneys into the urine. Clearance is calculated as 'CL=Dose / AUC0-30 days').
Time frame: From day 0 to day 30
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Total Plasma Clearance (CL) | 0.10 mL/h/kg | Standard Deviation 0.02 |
Secondary
Vital Signs - Blood Pressure (Systolic and Diastolic)
Time frame: Day 0 and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Factor XIII | Vital Signs - Blood Pressure (Systolic and Diastolic) | Systolic pre-dose | 98.5 mmHg | Standard Deviation 10.9 |
| Recombinant Factor XIII | Vital Signs - Blood Pressure (Systolic and Diastolic) | Systolic post-dose | 107.0 mmHg | Standard Deviation 13.7 |
| Recombinant Factor XIII | Vital Signs - Blood Pressure (Systolic and Diastolic) | Diastolic pre-dose | 59.8 mmHg | Standard Deviation 12.1 |
| Recombinant Factor XIII | Vital Signs - Blood Pressure (Systolic and Diastolic) | Diastolic post-dose | 64.0 mmHg | Standard Deviation 7.6 |
Secondary
Vital Signs - Pulse
Time frame: Day 0 and day 30
Population: Safety analysis population including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Factor XIII | Vital Signs - Pulse | pre-dose | 95.3 beats/minute | Standard Deviation 14.3 |
| Recombinant Factor XIII | Vital Signs - Pulse | post-dose | 113.2 beats/minute | Standard Deviation 10.6 |
Secondary
Volume of Distribution at Steady State (Vss)
Volume of distribution at steady state (Vss) is the theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it is in blood plasma at steady state. Steady state is achieved when all variables are constant in spite of ongoing processes.
Time frame: At steady state
Population: The full analysis set including all 6 children exposed to FXIII. All 6 children were exposed to one dose of trial product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Recombinant Factor XIII | Volume of Distribution at Steady State (Vss) | 66.07 mL/kg | Standard Deviation 14.32 |