Hemophilia A
Conditions
Keywords
hemophilia A
Brief summary
The study will be investigating pharmacokinetics, safety and efficacy in patients less than 12 years of age with severe hemophilia A that have been previously treated with Factor VIII products ( including blood products).
Interventions
BIOLOGICALMoroctocog alfa ( AF-CC)
Dosing is at the discretion of the Investigator
PROCEDURELaboratory tests
Factor VIII PK samples, Hematology, Chemistry and Coagulation testing, FactorVIII Inhibitor and Anti Factor VIII antibody
Sponsors
Pfizer
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
* Male subjects less than 12 years of age with a documented history of severe hemophilia A (FVIII:C less than 1%). * Subjects who are less than 6 years of age must have had at least 50 Exposure Days (EDs) to prior FVIII products (including blood products). * Subjects who are equal to or greater than 6 years of age must have had greater than 150 EDs to prior FVIII products (including blood products).
Exclusion criteria
* For laboratory assessments, any measured Bethesda inhibitor titer equal to or greater than 0.6 BU, regardless of the laboratory normal range, or any Bethesda inhibitor titer greater than ULN for the testing laboratory at the time of screening. * Any other bleeding disorder in addition to hemophilia A. * Treatment with any investigational drug or device within 30 days before the time of signing the parental informed consent/assent form. * Major surgery planned to occur during the course of the study. * Regular (e.g., daily; every other day) use of agents or medications known to influence platelet function such as aspirin or certain nonsteroidal anti-inflammatory drugs (NSAIDS). * Regular, concomitant therapy with immunomodulating drugs (e.g., intravenous immunoglobulin \[IVIG\], routine systemic corticosteroids), or currently receiving immune tolerance induction (ITI) for inhibitor treatment. * The subject is receiving treatment for HIV or hepatitis infection (unless the subject is on a stable antiviral regimen \[i.e., consistent treatment regimen for at least 3 months before the parental informed consent/assent form is signed\]). * Platelet count less than 100,000/µL. * Prothrombin time (PT) equal to or greater than 1.25 x ULN, or international normalized ratio (INR) equal to or greater than 1.5. * Known hypersensitivity to hamster protein.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Clinically Significant Factor VIII Inhibitor Development | Baseline up to Month 24 | Clinically significant factor VIII (FVIII) inhibitors were defined as a central laboratory confirmed positive inhibitor of greater than or equal to (\>=) 0.6 Bethesda units (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval and one of the following within 4 weeks before the initial or within 4 weeks following the second positive FVIII inhibitor sample collection: 1) the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, 2) \>=2 events indicating a decrease in the efficacy of the study treatment. Percentage of participants who developed clinically significant Factor VIII inhibitor after study drug administration were reported. |
| Incremental Recovery | Days 1, 15, 50, Months 6, 18 and Final visit (up to Month 24) | Incremental recovery was the increase in circulating FVIII activity for every international unit (IU) of ReFacto AF administered per kilogram of body weight. It was measured in international units per deciliter (IU/dL) per international units per kilogram (IU/kg). |
| Terminal Elimination Half Life of ReFacto AF (t1/2) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | T1/2 was the time for the plasma concentration of drug to decrease by one-half of its original concentration. |
| Clearance (CL) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Average Infusion Dose of ReFacto AF: All Participants | Baseline up to Month 24 | The average infusion dose (by weight) for each participant was calculated as his total factor FVIII consumption (in IU) divided by weight (in kg) divided by the number of infusions administered in total study duration. Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen. |
| Total Factor VIII Consumption: All Participants | Baseline up to Month 24 | Total factor VIII consumption for each participant was calculated by sum of the total amount of ReFacto AF (in IU) infused for each ReFacto AF infusion (recorded in the infusion log diary CRF). Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen. |
| Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Participants | Baseline up to Month 24 | LETE in on-demand setting was based on response to treatment of a bleeding episode. LETE in the on-demand setting occurred if participant recorded 2 successive no response ratings after 2 successive ReFacto AF infusions. Both infusions were to be administered at an interval of 24 hours for treatment of same bleeding event in absence of confounding factor which included: known presence or subsequent identification of a FVIII inhibitor, known inadequate dose for type and/or severity of bleed in opinion of investigator, delay of greater than 4 hours between onset of bleed to infusion, delay of greater than 24 hours before administration of a follow-up infusion, known compromised ReFacto AF, faulty administration of ReFacto AF, participant had an underlying, predisposing condition responsible for bleed in opinion of investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs),or ongoing trauma responsible for continued bleeding. |
| Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Participants | Baseline up to Month 24 | LETE in the prophylaxis setting occurred if there was a spontaneous bleed within 48 hours (\<=48 hours) after a regularly scheduled prophylactic dose of ReFacto AF (which was not used to treat a bleed) in the absence of confounding factors. Therefore, LETE in the prophylaxis setting is the occurrence of a bleed. Confounding factors include: Known presence or subsequent identification of a FVIII inhibitor, known inadequate prophylactic dose, known lack of adherence to the prescribed prophylaxis regimen, bleed occurs in a target joint identified at the start of the study, known compromised ReFacto AF, faulty administration of ReFacto AF, an underlying, predisposing condition responsible for the bleed in the opinion of the investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs) or traumatic injury responsible for bleeding. |
| Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Participants | Baseline up to Month 24 | LETE in the low recovery setting was defined as lower than expected recovery of FVIII (in the opinion of investigator), following the infusion of ReFacto AF in the absence of confounding factors for the low recovery. The only confounding factors for low recovery are as follows: known presence or subsequent identification of a FVIII inhibitor, known compromised ReFacto AF, faulty administration of ReFacto AF, including inadequate dosing. |
| Number of Participants Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Participants | Baseline up to Month 24 | Participants who met the dose escalation criteria were prescribed a higher dose and/or more frequent doses as per the investigator's discretion. |
| Mean Annualized Bleeding Rates (ABRs): All Participants | Baseline up to Month 24 | ABR for each participant was calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by the total therapy duration (in days), then multiplied by 365.25. ABR for the participants who reported following a primary or secondary prophylaxis, on-demand regimen or preventive regimen at baseline were reported. |
| Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. It was calculated as International units\*hour per milliliter (IU\*hr/mL). |
| Area Under the Plasma Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | AUClast is the area under the plasma versus time curve from time zero to time of last measurable concentration (AUClast) |
| Volume of Distribution at Steady State (Vss) | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state. |
| Mean Residence Time (MRT) of ReFacto AF | Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1 | MRT was calculated as AUMCinf / AUCinf-TI/2, where AUMCinf is the area under the first moment curve from time zero to infinity and TI was the duration of infusion. |
| Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Participants | Baseline up to 30 days after last study visit (Month 25) | An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events. |
| Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5) | 0.5 hour post-dose on Day 1 | — |
| Response to First On-Demand Treatment for New Bleeds: All Participants | Baseline up to Month 24 | A 4-point scale of assessment of 'on-demand' treatment (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) is defined as: 1. Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. 2. Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode;or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following infusion, with no additional infusion administered. 3. Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. 4. No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens. |
| Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Participants | Baseline up to Month 24 | The infusion log diary case report form (CRF) was used to determine the number of on-demand (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) ReFacto AF infusions administered to treat a new bleed. This was calculated by adding the initial for a new bleed (on-demand) infusion to any subsequent (on-demand) infusions for the same previously treated bleed (same bleed with same start date/time). |
| Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Participants | Baseline up to Month 24 | The number of breakthrough bleeds within 48 hours following a prophylaxis dose of ReFacto AF was summarized. The infusion log diary CRF was used to determine the number of infusions administered to treat a new bleed counting only those infusions which were administered \<=48 hours after an infusion marked as prophylaxis (which had no associated bleed). |
Countries
Finland, Georgia, Italy, Romania, Serbia, Spain, Sweden, Turkey (Türkiye), Ukraine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ReFacto AF: Less Than 6 Years Participants below 6 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC. | 18 |
| ReFacto AF: 6 to Less Than 12 Years Participants of 6 to 12 years of age were treated with IV injections of ReFacto AF at a dose and frequency prescribed by the investigator (minimum dose of 17 IU/kg up to maximum dose of 51 IU/kg) as per local standard of care in accordance with the SmPC. | 19 |
| Total | 37 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Parent/Legal guardian request | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | ReFacto AF: Less Than 6 Years | ReFacto AF: 6 to Less Than 12 Years | Total |
|---|---|---|---|
| Age, Continuous | 3.6 years STANDARD_DEVIATION 1.42 | 9.2 years STANDARD_DEVIATION 1.47 | 6.5 years STANDARD_DEVIATION 3.2 |
| Gender Female | 0 Participants | 0 Participants | 0 Participants |
| Gender Male | 18 Participants | 19 Participants | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 28 / 37 |
| serious Total, serious adverse events | 6 / 37 |
Outcome results
Primary
Clearance (CL)
Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood.
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Clearance (CL) | 4.406 milliliter per hour per kilogram | Geometric Coefficient of Variation 30 |
Primary
Incremental Recovery
Incremental recovery was the increase in circulating FVIII activity for every international unit (IU) of ReFacto AF administered per kilogram of body weight. It was measured in international units per deciliter (IU/dL) per international units per kilogram (IU/kg).
Time frame: Days 1, 15, 50, Months 6, 18 and Final visit (up to Month 24)
Population: The pharmacokinetic (PK) parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, n signifies participants who were evaluable at the specified time point for each arm respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Day 15 (n= 18, 17) | 1.23 (IU/dL)/(IU/kg) | Standard Deviation 0.65 |
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Month 6 (n= 2, 5) | 1.69 (IU/dL)/(IU/kg) | Standard Deviation 0.21 |
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Month 18 (n= 4, 5) | 1.81 (IU/dL)/(IU/kg) | Standard Deviation 0.405 |
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Day 1 (n= 17, 18) | 1.67 (IU/dL)/(IU/kg) | Standard Deviation 0.361 |
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Final Visit (n= 17, 17) | 1.98 (IU/dL)/(IU/kg) | Standard Deviation 1.454 |
| ReFacto AF: Less Than 6 Years | Incremental Recovery | Day 50 (n= 17, 18) | 1.66 (IU/dL)/(IU/kg) | Standard Deviation 0.626 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Final Visit (n= 17, 17) | 1.89 (IU/dL)/(IU/kg) | Standard Deviation 0.503 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Day 1 (n= 17, 18) | 1.97 (IU/dL)/(IU/kg) | Standard Deviation 0.437 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Day 15 (n= 18, 17) | 1.91 (IU/dL)/(IU/kg) | Standard Deviation 0.423 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Day 50 (n= 17, 18) | 1.96 (IU/dL)/(IU/kg) | Standard Deviation 0.586 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Month 18 (n= 4, 5) | 1.80 (IU/dL)/(IU/kg) | Standard Deviation 0.493 |
| ReFacto AF: 6 to Less Than 12 Years | Incremental Recovery | Month 6 (n= 2, 5) | 2.17 (IU/dL)/(IU/kg) | Standard Deviation 0.379 |
Primary
Percentage of Participants With Clinically Significant Factor VIII Inhibitor Development
Clinically significant factor VIII (FVIII) inhibitors were defined as a central laboratory confirmed positive inhibitor of greater than or equal to (\>=) 0.6 Bethesda units (BU) using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval and one of the following within 4 weeks before the initial or within 4 weeks following the second positive FVIII inhibitor sample collection: 1) the need for the participant to administer alternative hemostatic products in order to achieve sufficient efficacy, 2) \>=2 events indicating a decrease in the efficacy of the study treatment. Percentage of participants who developed clinically significant Factor VIII inhibitor after study drug administration were reported.
Time frame: Baseline up to Month 24
Population: Safety analysis population included all enrolled participants who received at least 1 dose of ReFacto AF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Percentage of Participants With Clinically Significant Factor VIII Inhibitor Development | 0.00 percentage of participants |
| ReFacto AF: 6 to Less Than 12 Years | Percentage of Participants With Clinically Significant Factor VIII Inhibitor Development | 0.00 percentage of participants |
Primary
Terminal Elimination Half Life of ReFacto AF (t1/2)
T1/2 was the time for the plasma concentration of drug to decrease by one-half of its original concentration.
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Terminal Elimination Half Life of ReFacto AF (t1/2) | 9.12 hours | Standard Deviation 1.9429 |
Secondary
Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf)
AUCinf is the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. It was calculated as International units\*hour per milliliter (IU\*hr/mL).
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Area Under the Plasma Time Curve From Time 0 Extrapolated to Infinite Time (AUCinf) | 9.89 IU*hr/mL | Geometric Coefficient of Variation 41 |
Secondary
Area Under the Plasma Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast)
AUClast is the area under the plasma versus time curve from time zero to time of last measurable concentration (AUClast)
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Area Under the Plasma Time Curve From Time Zero to Time of Last Measurable Concentration (AUClast) | 9.49 IU*hr/mL | Geometric Coefficient of Variation 41 |
Secondary
Average Infusion Dose of ReFacto AF: All Participants
The average infusion dose (by weight) for each participant was calculated as his total factor FVIII consumption (in IU) divided by weight (in kg) divided by the number of infusions administered in total study duration. Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, n signifies participants who were evaluable for each specified baseline category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Average Infusion Dose of ReFacto AF: All Participants | With prophylaxis regimen at baseline (n= 22) | 37.0 IU/kg | Standard Deviation 8.7 |
| ReFacto AF: Less Than 6 Years | Average Infusion Dose of ReFacto AF: All Participants | With non-prophylaxis regimen at baseline (n= 15) | 29.5 IU/kg | Standard Deviation 7.61 |
Secondary
Mean Annualized Bleeding Rates (ABRs): All Participants
ABR for each participant was calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by the total therapy duration (in days), then multiplied by 365.25. ABR for the participants who reported following a primary or secondary prophylaxis, on-demand regimen or preventive regimen at baseline were reported.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and n signifies participants who were evaluable at the specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Mean Annualized Bleeding Rates (ABRs): All Participants | Preventive regimen (n=0) | NA bleeds per year | — |
| ReFacto AF: Less Than 6 Years | Mean Annualized Bleeding Rates (ABRs): All Participants | On-demand regimen (n=14) | 27.51 bleeds per year | Standard Deviation 20.387 |
| ReFacto AF: Less Than 6 Years | Mean Annualized Bleeding Rates (ABRs): All Participants | Primary or secondary prophylaxis regimen (n=22) | 4.18 bleeds per year | Standard Deviation 3.849 |
Secondary
Mean Residence Time (MRT) of ReFacto AF
MRT was calculated as AUMCinf / AUCinf-TI/2, where AUMCinf is the area under the first moment curve from time zero to infinity and TI was the duration of infusion.
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Mean Residence Time (MRT) of ReFacto AF | 13.91 hour |
Secondary
Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Participants
The number of breakthrough bleeds within 48 hours following a prophylaxis dose of ReFacto AF was summarized. The infusion log diary CRF was used to determine the number of infusions administered to treat a new bleed counting only those infusions which were administered \<=48 hours after an infusion marked as prophylaxis (which had no associated bleed).
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Breakthrough Bleeds Within 48 Hours of a Prophylaxis Dose of ReFacto AF: All Participants | 2.0 breakthrough bleeds | Standard Deviation 1.15 |
Secondary
Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Participants
LETE in on-demand setting was based on response to treatment of a bleeding episode. LETE in the on-demand setting occurred if participant recorded 2 successive no response ratings after 2 successive ReFacto AF infusions. Both infusions were to be administered at an interval of 24 hours for treatment of same bleeding event in absence of confounding factor which included: known presence or subsequent identification of a FVIII inhibitor, known inadequate dose for type and/or severity of bleed in opinion of investigator, delay of greater than 4 hours between onset of bleed to infusion, delay of greater than 24 hours before administration of a follow-up infusion, known compromised ReFacto AF, faulty administration of ReFacto AF, participant had an underlying, predisposing condition responsible for bleed in opinion of investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs),or ongoing trauma responsible for continued bleeding.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and received treatment for at least one bleed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the On-Demand Setting: All Participants | 0 LETE bleeds |
Secondary
Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Participants
LETE in the prophylaxis setting occurred if there was a spontaneous bleed within 48 hours (\<=48 hours) after a regularly scheduled prophylactic dose of ReFacto AF (which was not used to treat a bleed) in the absence of confounding factors. Therefore, LETE in the prophylaxis setting is the occurrence of a bleed. Confounding factors include: Known presence or subsequent identification of a FVIII inhibitor, known inadequate prophylactic dose, known lack of adherence to the prescribed prophylaxis regimen, bleed occurs in a target joint identified at the start of the study, known compromised ReFacto AF, faulty administration of ReFacto AF, an underlying, predisposing condition responsible for the bleed in the opinion of the investigator (e.g., kidney stones or use of medications known to impair platelet function, such as aspirin or NSAIDs) or traumatic injury responsible for bleeding.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Participants who received at least 1 prophylaxis dose of ReFacto AF were reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Less-Than-Expected-Therapeutic Effect (LETE) Bleeds in the Prophylaxis Setting: All Participants | 2 LETE bleeds |
Secondary
Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Participants
LETE in the low recovery setting was defined as lower than expected recovery of FVIII (in the opinion of investigator), following the infusion of ReFacto AF in the absence of confounding factors for the low recovery. The only confounding factors for low recovery are as follows: known presence or subsequent identification of a FVIII inhibitor, known compromised ReFacto AF, faulty administration of ReFacto AF, including inadequate dosing.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Occurrences of Less-Than-Expected-Therapeutic Effect (LETE) in the Low Recovery Setting: All Participants | 9 LETE bleeds |
Secondary
Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Participants
The infusion log diary case report form (CRF) was used to determine the number of on-demand (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) ReFacto AF infusions administered to treat a new bleed. This was calculated by adding the initial for a new bleed (on-demand) infusion to any subsequent (on-demand) infusions for the same previously treated bleed (same bleed with same start date/time).
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of On-Demand ReFacto AF Infusions to Treat a New Bleed: All Participants | 1.1 infusions | Standard Deviation 0.55 |
Secondary
Number of Participants Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Participants
Participants who met the dose escalation criteria were prescribed a higher dose and/or more frequent doses as per the investigator's discretion.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Participants who used a prophylaxis regimen were analyzed for this outcome measure.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Participants Requiring Escalated Dose of Prescribed Regimen During the Treatment Period: All Participants | 5 participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Participants
An adverse event (AE) was any untoward medical occurrence in a participant who received study treatment without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death, initial or prolonged inpatient hospitalization, life-threatening experience (immediate risk of dying), persistent or significant disability or incapacity, congenital anomaly. Treatment-emergent are events between first dose of study drug and up to 30 days after last dose that were absent before treatment or that worsened relative to pretreatment state. AEs included both serious and non-serious adverse events.
Time frame: Baseline up to 30 days after last study visit (Month 25)
Population: Safety analysis population included all enrolled participants who received at least 1 dose of ReFacto AF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Participants | AEs | 28 participants |
| ReFacto AF: Less Than 6 Years | Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs): All Participants | SAEs | 6 participants |
Secondary
Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5)
Time frame: 0.5 hour post-dose on Day 1
Population: The PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5) | 0.752 IU/mL | Geometric Coefficient of Variation 18 |
| ReFacto AF: 6 to Less Than 12 Years | Plasma Concentration of Factor VIII at 0.5 Hour Post-dose (C0.5) | 0.903 IU/mL | Geometric Coefficient of Variation 45 |
Secondary
Response to First On-Demand Treatment for New Bleeds: All Participants
A 4-point scale of assessment of 'on-demand' treatment (administration of an unscheduled bolus infusion of Refacto-AF to stop bleeding) is defined as: 1. Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered. 2. Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode;or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following infusion, with no additional infusion administered. 3. Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode. 4. No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure and received at least 1 dose of ReFacto AF for at least one bleeding episode.
| Arm | Measure | Group | Value (NUMBER) | Dispersion |
|---|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Response to First On-Demand Treatment for New Bleeds: All Participants | Excellent | 713 responses | 20.387 |
| ReFacto AF: Less Than 6 Years | Response to First On-Demand Treatment for New Bleeds: All Participants | Good | 73 responses | — |
| ReFacto AF: Less Than 6 Years | Response to First On-Demand Treatment for New Bleeds: All Participants | Moderate | 16 responses | 3.849 |
| ReFacto AF: Less Than 6 Years | Response to First On-Demand Treatment for New Bleeds: All Participants | Data Not Recorded | 2 responses | — |
Secondary
Total Factor VIII Consumption: All Participants
Total factor VIII consumption for each participant was calculated by sum of the total amount of ReFacto AF (in IU) infused for each ReFacto AF infusion (recorded in the infusion log diary CRF). Data was reported separately for participants classified at baseline as following non-prophylaxis regimen (for example: on-demand regimen, preventive, or not specified), and participants classified at baseline following a primary or secondary prophylaxis regimen.
Time frame: Baseline up to Month 24
Population: Efficacy analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, n signifies participants who were evaluable for each specified baseline category.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Total Factor VIII Consumption: All Participants | With Prophylaxis regimen at baseline (n= 22) | 97959.4 IU | Standard Deviation 48474.09 |
| ReFacto AF: Less Than 6 Years | Total Factor VIII Consumption: All Participants | With non-prophylaxis regimen at baseline (n= 15) | 84051.7 IU | Standard Deviation 47362.6 |
Secondary
Volume of Distribution at Steady State (Vss)
Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Steady state volume of distribution (Vss) was the apparent volume of distribution at steady-state.
Time frame: Pre-dose, 0.5, 1, 3, 6, 9, 24, 28, 32, 48 hours post-dose on Day 1
Population: PK parameter analysis population included all enrolled participants who received at least 1 dose of ReFacto AF. Here, number of participants analyzed signifies participants who were evaluable for this outcome measure. Data was not planned to be collected and analyzed for reporting arm ReFacto AF: Less Than 6 Years, as pre-specified in protocol.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| ReFacto AF: Less Than 6 Years | Volume of Distribution at Steady State (Vss) | 56.42 mL/kg | Geometric Coefficient of Variation 15 |