Congenital Hemophilia A
Conditions
Brief summary
This is an international, multicenter, open-label study to assess the efficacy, safety, and pharmacokinetic (PK) profile of rVIII-SingleChain in pediatric patients with severe hemophilia A. A minimum of 25 previously treated subjects ≥ 6 to \< 12 years of age and at least 25 subjects \< 6 years of age who have undergone \> 50 exposure days (EDs) with a previous Factor VIII (FVIII) product are planned to be enrolled. Subjects will be assigned to either an on-demand or prophylaxis treatment regimen and will receive rVIII-SingleChain at a dose to be determined by the investigator. Hemostatic efficacy will be assessed by the subject/caregiver and the investigator who will assess overall efficacy by a 4-point scale.
Interventions
BIOLOGICALrVIII-SingleChain
Sponsors
CSL Behring
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 11 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of severe hemophilia A defined as \< 1% Factor VIII (FVIII) concentration (FVIII:C) documented in medical records, * Males \< 12 years of age, * Subjects who have received \> 50 EDs with a FVIII product, * Prior PK data (at least incremental recovery and half-life) from previous FVIII exposure for subjects participating in the PK part * Investigator believes that the subject is willing and able to adhere to all protocol requirements. Investigator believes that the subject's parent(s) or legally acceptable representative(s) is / are willing and able to adhere to all protocol requirements.
Exclusion criteria
* Any history of or current FVIII inhibitors * Use of an Investigational Medical Product (IMP) within 30 days prior to the first rVIII-SingleChain administration, * Administration of any cryoprecipitate, whole blood or plasma within 30 days prior to administration of rVIII-SingleChain, * Known hypersensitivity (allergic reaction or anaphylaxis) to any FVIII product or hamster protein, * Subject currently receiving IV immunomodulating agents such as immunoglobulin or chronic systemic corticosteroid treatment, * Subject with serum aspartate aminotransferase (AST) or serum alanine aminotransferase (ALT) values \>5 times (x) the upper limit of normal (ULN) at Screening, * Subjects with serum creatinine values \>2 x ULN at Screening, * Evidence of thrombosis, including deep vein thrombosis, stroke, pulmonary embolism, myocardial infarction and arterial embolus within 3 months before Day 1, * Experienced life-threatening bleeding episode or had major surgery or an orthopedic surgical procedure during the 3 months before rVIII-SingleChain administration.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Treatment Success | Up to 1 year | Rate of treatment success where treatment success of a bleeding episode is defined as a rating of excellent or good based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. | Up to 1 year | — |
| Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month | Up to 1 year | — |
| Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year | Up to 1 year | — |
| Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event | Up to 1 year | — |
| Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month | Up to 1 year | — |
| Annualized Bleeding Rate | Up to 1 year | The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens. |
| Incremental Recovery | At 1 hour after the start of infusion | Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay. |
| Half-life (t1/2) of rVIII-SingleChain | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. |
| Area Under the Concentration Curve (AUC) | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. |
| Clearance (Cl) of rVIII-SingleChain | Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing. | Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay. |
| Number of Subjects With Inhibitor Formation to rVIII-SingleChain | At screening, then after dosing at approximately monthly intervals for 6 months, then every 3 months until reaching 50 EDs, and at the end of study visit (up to approximately 12 months). | The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug. |
| Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year | Up to 1 year | — |
Countries
Australia, Austria, France, Georgia, Germany, Italy, Lebanon, Malaysia, Netherlands, Philippines, Poland, Portugal, Romania, Spain, Switzerland, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This multicenter, multinational study enrolled subjects at 37 participating study centers in Australia, Europe, Georgia, Lebanon, Malaysia, Philippines, Switzerland, Thailand, Turkey, Ukraine, and the United States.
Pre-assignment details
Screening took place 4 to 28 days prior to first dose of study product (rVIII-SingleChain). A total of 88 subjects were screened, 4 of these did not fulfill all eligibility criteria and were therefore screening failures.
Participants by arm
| Arm | Count |
|---|---|
| rVIII-SingleChain Subjects were assigned to either an on-demand or prophylaxis regimen and received rVIII-SingleChain as an IV infusion. Subjects assigned to a prophylaxis regimen were treated with 15 to 50 IU/kg of rVIII-SingleChain every second day or 2 to 3 times per week, or at the investigator's discretion, based on available PK data, the FVIII treatment regimen used before enrollment and/or the subject's bleeding phenotype. The dose for on-demand treatment of a bleeding episode was based on the recommendations of the WFH, with a minimum dose of 15 IU/kg. All subjects were to be treated for a minimum of 50 EDs. For the PK evaluation, the subjects received a single IV dose of 50 IU/kg of rVIII-SingleChain on Day 1 at the start of the PK evaluation period. | 84 |
| Total | 84 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse event, non-fatal | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Planned age group closure - no's reached | 17 |
Baseline characteristics
| Characteristic | rVIII-SingleChain |
|---|---|
| Age, Categorical <=18 years | 84 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 6.6 years STANDARD_DEVIATION 3.11 |
| Gender Female | 0 Participants |
| Gender Male | 84 Participants |
| Treatment modality of FVIII therapy before enrollment On-Demand | 24 participants |
| Treatment modality of FVIII therapy before enrollment Prophylaxis | 60 participants |
| Type of FVIII product used before enrollment Plasma product | 33 participants |
| Type of FVIII product used before enrollment Recombinant Product | 49 participants |
| Type of FVIII product used before enrollment Unknown | 2 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 84 |
| serious Total, serious adverse events | 9 / 84 |
Outcome results
Primary
Treatment Success
Rate of treatment success where treatment success of a bleeding episode is defined as a rating of excellent or good based on the investigator's overall clinical assessment of hemostatic efficacy (using a 4-point scale of excellent, good, moderate or poor/no response) on the on-demand and prophylaxis regimens combined. The rate of success was based on the number of treated bleeding events; there were 347 treated bleeding events in the Efficacy Population.
Time frame: Up to 1 year
Population: Efficacy Population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efficacy Population | Treatment Success | 96.3 Percentage of treated bleeding events |
Secondary
Annualized Bleeding Rate
The annualized bleeding rate was defined as the number of bleeding episodes requiring treatment divided by the efficacy evaluation period in days, x 365.25, and is presented separately for the on-demand regimen and the prophylaxis regimens.
Time frame: Up to 1 year
Population: The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Annualized Bleeding Rate | 78.56 Treated bleeding episodes per year |
| Prophylaxis | Annualized Bleeding Rate | 3.69 Treated bleeding episodes per year |
Secondary
Area Under the Concentration Curve (AUC)
AUC to the last sample with quantifiable drug concentration (AUC0-t), baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efficacy Population | Area Under the Concentration Curve (AUC) | 1050 IU*h/dL | Standard Deviation 286 |
Secondary
Clearance (Cl) of rVIII-SingleChain
Clearance (Cl) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efficacy Population | Clearance (Cl) of rVIII-SingleChain | 4.86 mL/h/kg | Standard Deviation 1.43 |
Secondary
Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event
Time frame: Up to 1 year
Population: The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event | 25.9 IU/kg per event |
| Prophylaxis | Consumption of rVIII-SingleChain - IU/kg Per Bleeding Event | 37.0 IU/kg per event |
Secondary
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month
Time frame: Up to 1 year
Population: The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month | 202 IU/kg per subject per month |
| Prophylaxis | Consumption of rVIII-SingleChain - IU/kg Per Subject Per Month | 378 IU/kg per subject per month |
Secondary
Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year
Time frame: Up to 1 year
Population: The Efficacy Population comprised all subjects who received at least 1 rVIII-SingleChain dose for prophylaxis or on-demand treatment. One subject was excluded from the efficacy population because of a pre-existing inhibitor to FVIII (confirmed by reexamination of a screening sample initially reported as negative due to laboratory error).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year | 2429 IU/kg per subject per year |
| Prophylaxis | Consumption of rVIII-SingleChain - IU/kg Per Subject Per Year | 4541 IU/kg per subject per year |
Secondary
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month
Time frame: Up to 1 year
Population: Subjects assigned to the on-demand treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Month | 7.58 number of infusion per subject per month |
Secondary
Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year
Time frame: Up to 1 year
Population: Subjects assigned to the on-demand treatment regimen.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Efficacy Population | Consumption of rVIII-SingleChain (On-demand Regimen) - Number of Infusions Per Subject Per Year | 90.95 number of infusions per subject per year |
Secondary
Half-life (t1/2) of rVIII-SingleChain
Half-life (t1/2) of rVIII-SingleChain, baseline uncorrected; plasma FVIII activity measured using the chromogenic substrate assay.
Time frame: Immediately before dosing, and at approximately 1, 5, 10, 24, and 48 hours after dosing.
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efficacy Population | Half-life (t1/2) of rVIII-SingleChain | 10.3 hour | Standard Deviation 2.51 |
Secondary
Incremental Recovery
Incremental recovery expressed as (IU/dL)/(IU/kg) corrected for subject's predose plasma FVIII activity measured using the chromogenic substrate assay.
Time frame: At 1 hour after the start of infusion
Population: PK Population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Efficacy Population | Incremental Recovery | 1.63 (IU/dL)/(IU/kg) | Standard Deviation 0.329 |
Secondary
Number of Subjects With Inhibitor Formation to rVIII-SingleChain
The number of subjects who develop inhibitors to rVIII-SingleChain, defined as a rVIII-SingleChain antibody titer of at least 0.6 Bethesda Units (BU) per mL after receiving study drug.
Time frame: At screening, then after dosing at approximately monthly intervals for 6 months, then every 3 months until reaching 50 EDs, and at the end of study visit (up to approximately 12 months).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Efficacy Population | Number of Subjects With Inhibitor Formation to rVIII-SingleChain | 0 participants |
Secondary
Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis.
Time frame: Up to 1 year
Population: Efficacy Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Efficacy Population | Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. | Requiring > 3 infusions | 2.0 Percentage (%) of bleeding episodes |
| Efficacy Population | Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. | Requiring 1 infusion | 85.9 Percentage (%) of bleeding episodes |
| Efficacy Population | Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. | Requiring 2 infusions | 9.8 Percentage (%) of bleeding episodes |
| Efficacy Population | Percentage of Bleeding Episodes Requiring 1, 2, 3, or More Than 3 Infusions of rVIII-SingleChain to Achieve Hemostasis. | Requiring 3 infusions | 2.3 Percentage (%) of bleeding episodes |