Hemophilia A
Conditions
Keywords
Factor VIII Deficiency
Brief summary
The purpose of this study is to evaluate whether Antihemophilic factor, recombinant, manufactured protein-free (rAHF-PFM) is effective and safe in the treatment of hemophilia A patients who have not been treated with factor VIII (FVIII) before.
Interventions
BIOLOGICALRecombinant Antihemophilic Factor Manufactured and Formulated without Added Human or Animal Proteins (rAHF-PFM)
Treatment regimens were determined by the investigator, and may have been any combination of standard prophylaxis (25 to 50 IU/kg body weight, 3 to 4 times per week), investigator-determined prophylaxis, and/or on-demand treatment (dose selected by investigator). The treatment of bleeding episodes and perioperative management was at the discretion of the investigator and consistent with the institution's standard of care. For incremental recovery assessments, a single infusion at 50 +/- 5 IU/kg was to be given. Immune tolerance induction (ITI) therapy for subjects who developed factor VIII inhibitors was at the discretion of the investigator, based on the institution's guidelines or described in peer-reviewed literature, and was to be approved by the sponsor's medical director. rAHF-PFM was to be administered intravenously via bolus infusion, except for perioperative management when it may have been given either by continuous or bolus infusion.
Sponsors
Baxalta now part of Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 6 Years
Healthy volunteers
No
Inclusion criteria
* The subject has severe or moderately severe hemophilia A as defined by a baseline factor VIII level \<= 2% of normal, as documented at screening * The subject is \< 6 years of age * The subject's legally authorized representative has provided written informed consent
Exclusion criteria
* The subject has a history of exposure to factor VIII other than rAHF PFM or more than 3 infusions of commercially available rAHF PFM (i.e., ADVATE) within 28 days prior to screening, as determined by the subject's medical history. Any infusion of factor VIII replacement products prior to the 28-day period excludes the subject from participation * The subject has received more than 3 infusions of rAHF PFM (commercially available and/or study product) between screening and prior to the initial recovery infusion * The subject has a detectable inhibitor to factor VIII, as measured in the screening sample by the Nijmegen assay in the central laboratory * The subject has a history of inhibitor to factor VIII at any time prior to screening * The subject has a known hypersensitivity to rAHF PFM * The subject has any 1 of the following laboratory abnormalities at the time of screening: 1. Platelet count \< 100,000/mm\^3 2. Hemoglobin concentration \< 10 g/dL (100 g/L) 3. Serum creatinine \> 1.5 times the upper limit of normal (ULN) for age 4. Total bilirubin \> 2 times the ULN for age * The subject has an inherited or acquired hemostatic defect other than hemophilia A (e.g., qualitative platelet defect or von Willebrand's disease) * The subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV), as determined by the subject's medical history * At the time of enrollment, the subject has a clinically significant chronic disease other than hemophilia A * The subject is currently participating in another investigational drug study, or has participated in any clinical study involving an investigational drug within 120 days of the screening visit * The subject (or the subject's legally authorized representative) is identified by the investigator as being unable or unwilling to cooperate with study procedures * The subject has received any blood product, including packed red blood cells (RBC), platelets, plasma, or cryoprecipitate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Factor VIII Inhibitor Development | Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first) | Percentage of treated participants who developed factor VIII inhibitors |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Hemostasis for Treatment of Bleeding Episodes | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | Number of rAHF-PFM-treated bleeding episodes with treater assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within \ 8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within \ 8 hrs after infusion. Possibly requires \>1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within \ 8 hrs after infusion. Requires \>1 infusion for complete resolution; or None: No improvement or condition worsens. |
| Annualized Rate of Bleeding Episodes | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | Number of bleeding episodes per subject annualized over 1 year for all etiologies |
| Weekly rAHF-PFM Utilization | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management. rAHF-PFM dose determined by the investigator (ie: standard regimen \[25-50 IU/kg body weight, 3-4 times per week\]; modified prophylactic regimen \[dose and frequency selected by investigator\] or on-demand treatment \[dose selected by investigator\]). Dosing to treat BEs was at investigator's discretion and in accordance with institution's standard of care. rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion. |
| In Vivo Incremental Recovery | 30 minutes pre-infusion to 30 minutes post-infusion | Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. |
| Bleeding Episodes Treated With 1 to ≥4 Infusions | Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first) | The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis |
| Assessment of Postoperative Hemostasis | Assessed at the time of discharge from hospital or clinic | Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale: Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure Fair: hemostasis was clearly \< optimal for matched procedure, without need to change regimen None: bleeding from inadequate response with proper dosing, necessitating a change in regimen |
| Assessment of Blood Loss During Surgical Procedures | Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded | Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records) |
| Adverse Events Deemed Related to Treatment | Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first) | Percentage of participants who reported AEs deemed related to treatment with rAHF-PFM |
| Development of Antibodies to Heterologous Proteins | Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit. | Percentage of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF) |
| Assessment of Intra-operative Hemostasis | Assessed at the time of discharge from recovery room | Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale: Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals Good: \> average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals Fair: \> maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen |
Countries
Austria, Canada, France, Germany, Italy, Puerto Rico, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Recruitment was conducted in the U.S., Canada, and Europe at 24 study sites.
Pre-assignment details
Participants screened for maximum 21 days. Study was not randomized; it was an open-label evaluation. Prior to initial infusion, a minimum washout period of 3 days was required. 11 participants who enrolled did not receive any rAHF-PFM infusions (3 withdrew consent, 6 screen failures, 1 non-compliance with screening, 1 pre-existing low hemoglobin)
Participants by arm
| Arm | Count |
|---|---|
| PUPs | 55 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Enrolled in another study | 1 |
| Overall Study | Inclusion not met- baseline FVIII value | 1 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Met exclusion criteria | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 6 |
Baseline characteristics
| Characteristic | PUPs |
|---|---|
| Age, Customized ≥13 months | 8 Participants |
| Age, Customized 6-12 months | 26 Participants |
| Age, Customized <6 months | 21 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 52 / 55 |
| serious Total, serious adverse events | 28 / 55 |
Outcome results
Primary
Factor VIII Inhibitor Development
Percentage of treated participants who developed factor VIII inhibitors
Time frame: Assessed during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants who received at least 1 infusion of rAHF-PFM
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PUPs | Factor VIII Inhibitor Development | 29.1 percentage |
Secondary
Adverse Events Deemed Related to Treatment
Percentage of participants who reported AEs deemed related to treatment with rAHF-PFM
Time frame: Reported during the study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants who received at least 1 infusion of rAHF-PFM
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PUPs | Adverse Events Deemed Related to Treatment | 36.4 Percentage of Participants |
Secondary
Annualized Rate of Bleeding Episodes
Number of bleeding episodes per subject annualized over 1 year for all etiologies
Time frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants treated for at least 3 months with investigator-defined on-demand treatment (for dose) or prophylaxis (for dose and infusion frequency) for \>80% of the treatment period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PUPs | Annualized Rate of Bleeding Episodes | 4.95 bleeding episodes per subject per year |
Secondary
Assessment of Blood Loss During Surgical Procedures
Percentage of actual intraoperative blood loss compared to preoperatively predicted average and maximal blood loss in hemostatically normal matched individuals (from institutional blood bank records)
Time frame: Predicted volumes preoperatively estimated and actual volumes intraoperatively recorded
Population: Number of participants who underwent a surgical procedure with blood loss assessments
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| PUPs | Assessment of Blood Loss During Surgical Procedures | Blood loss as percentage of predicted average | 50.0 Percentage Blood Loss |
| PUPs | Assessment of Blood Loss During Surgical Procedures | Blood loss as percentage of predicted maximal | 20.0 Percentage Blood Loss |
Secondary
Assessment of Hemostasis for Treatment of Bleeding Episodes
Number of rAHF-PFM-treated bleeding episodes with treater assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within \ 8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within \ 8 hrs after infusion. Possibly requires \>1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within \ 8 hrs after infusion. Requires \>1 infusion for complete resolution; or None: No improvement or condition worsens.
Time frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants who received at least 1 infusion of rAHF-PFM and had at least 1 treated bleeding episode. The 1 rating of none was for the first 2 infusions, the last infusion was rated as good.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Assessment of Hemostasis for Treatment of Bleeding Episodes | Excellent | 258 bleeding episodes |
| PUPs | Assessment of Hemostasis for Treatment of Bleeding Episodes | Good | 177 bleeding episodes |
| PUPs | Assessment of Hemostasis for Treatment of Bleeding Episodes | Fair | 30 bleeding episodes |
| PUPs | Assessment of Hemostasis for Treatment of Bleeding Episodes | None | 1 bleeding episodes |
| PUPs | Assessment of Hemostasis for Treatment of Bleeding Episodes | Unknown/not assessed | 51 bleeding episodes |
Secondary
Assessment of Intra-operative Hemostasis
Number of surgical procedures managed with rAHF-PFM and with surgeon's assessment of hemostasis based on a 4-point ordinal scale: Excellent: ≤ average predicted blood loss for matched procedures in healthy individuals Good: \> average predicted blood loss, but ≤ maximal predicted blood loss for matched procedures in healthy individuals Fair: \> maximal predicted blood loss for matched procedures in healthy individuals, and hemostasis was achieved None: uncontrolled hemostasis with proper dosing, necessitating a change in treatment regimen
Time frame: Assessed at the time of discharge from recovery room
Population: Number of participants who underwent a surgical procedure with an intraoperative assessment of hemostatic efficacy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Assessment of Intra-operative Hemostasis | Excellent | 18 Procedures |
| PUPs | Assessment of Intra-operative Hemostasis | Good | 4 Procedures |
| PUPs | Assessment of Intra-operative Hemostasis | Not Applicable | 0 Procedures |
| PUPs | Assessment of Intra-operative Hemostasis | Not Done | 0 Procedures |
Secondary
Assessment of Postoperative Hemostasis
Number of surgical procedures managed with rAHF-PFM and with investigator's assessment of hemostasis based on a 4-point ordinal scale: Excellent: hemostasis was as good as or better than other licensed factor VIII products for matched procedure Good: hemostasis was probably as good as other licensed factor VIII products for matched procedure Fair: hemostasis was clearly \< optimal for matched procedure, without need to change regimen None: bleeding from inadequate response with proper dosing, necessitating a change in regimen
Time frame: Assessed at the time of discharge from hospital or clinic
Population: Number of participants who underwent a surgical procedure with a postoperative assessment of hemostatic efficacy
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Assessment of Postoperative Hemostasis | Excellent | 23 Procedures |
| PUPs | Assessment of Postoperative Hemostasis | Good | 2 Procedures |
| PUPs | Assessment of Postoperative Hemostasis | Not Applicable | 1 Procedures |
| PUPs | Assessment of Postoperative Hemostasis | Not Done | 1 Procedures |
Secondary
Bleeding Episodes Treated With 1 to ≥4 Infusions
The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis
Time frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants who received at least 1 infusion of rAHF-PFM for the treatment of bleeding episodes
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Bleeding Episodes Treated With 1 to ≥4 Infusions | 1 infusion | 356 Bleeding episodes |
| PUPs | Bleeding Episodes Treated With 1 to ≥4 Infusions | 2 infusions | 107 Bleeding episodes |
| PUPs | Bleeding Episodes Treated With 1 to ≥4 Infusions | 3 infusions | 35 Bleeding episodes |
| PUPs | Bleeding Episodes Treated With 1 to ≥4 Infusions | 4 or more infusions | 19 Bleeding episodes |
Secondary
Development of Antibodies to Heterologous Proteins
Percentage of treated participants who developed antibodies to heterologous proteins (ie, Chinese Hamster Ovary Cell Protein, Murine IgG, or Recombinant Human VWF)
Time frame: Assessed at baseline, throughout the duration of the study, which was to be at least 75 exposure days or 3 years (whichever came first), and at the termination visit.
Population: Participants who received at least 1 infusion of rAHF-PFM and had assessments of heterologous antibodies
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Development of Antibodies to Heterologous Proteins | Antibodies to Murine IgG | 0.00 Percentage of Participants |
| PUPs | Development of Antibodies to Heterologous Proteins | Antibodies to Chinese Hamster Ovary Cell Protein | 0.00 Percentage of Participants |
| PUPs | Development of Antibodies to Heterologous Proteins | Antibodies to Recombinant Human VWF (n=54) | 0.00 Percentage of Participants |
Secondary
In Vivo Incremental Recovery
Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits.
Time frame: 30 minutes pre-infusion to 30 minutes post-infusion
Population: Participants who received pharmacokinetic rAHF-PFM infusions, did not develop inhibitors, and had assessments
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PUPs | In Vivo Incremental Recovery | 1.81 IU/dL per IU/kg |
| PUPs -During On-Demand Treatment | In Vivo Incremental Recovery | 1.71 IU/dL per IU/kg |
Secondary
Weekly rAHF-PFM Utilization
Weight-Adjusted Weekly Dose for Prophylaxis, On-Demand Treatment, and Perioperative Management. rAHF-PFM dose determined by the investigator (ie: standard regimen \[25-50 IU/kg body weight, 3-4 times per week\]; modified prophylactic regimen \[dose and frequency selected by investigator\] or on-demand treatment \[dose selected by investigator\]). Dosing to treat BEs was at investigator's discretion and in accordance with institution's standard of care. rAHF-PFM was administered I.V. via bolus infusion, except for perioperative management when it was given either by continuous or bolus infusion.
Time frame: Reported during study period which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Participants treated for at least 3 months with investigator-defined on-demand treatment (for dose) or prophylaxis (for dose and infusion frequency) for \>80% of the treatment period
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PUPs | Weekly rAHF-PFM Utilization | 87.1 IU/kg |
| PUPs -During On-Demand Treatment | Weekly rAHF-PFM Utilization | 12.5 IU/kg |
| PUPs -During Perioperative Management | Weekly rAHF-PFM Utilization | 606.4 IU/kg |
Post Hoc
Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors
Number of treated participants who developed an inhibitor
Time frame: Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | Has Family History of Inhibitors | 6 Participants |
| PUPs | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | Unknown Family History of Inhibitors | 2 Participants |
| PUPs | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | No Family History of Inhibitors | 26 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | Has Family History of Inhibitors | 8 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | Unknown Family History of Inhibitors | 1 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Genetic Risk Factor- Family History of Inhibitors | No Family History of Inhibitors | 7 Participants |
95% CI: [1.29, 19.06]
Post Hoc
Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs))
Immunogenicity Analysis Set- Participants with 5 consecutive study days of a mean infusion dose of FVIII \>50 IU/kg within ≤20 EDs who developed an inhibitor
Time frame: Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs)) | Received intensive treatment & high dose | 4 Participants |
| PUPs | Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs)) | No intensive treatment & high dose | 30 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs)) | Received intensive treatment & high dose | 6 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Number of Participants With Intensive Treatment and High Dose (≤20 Exposure Days (EDs)) | No intensive treatment & high dose | 10 Participants |
95% CI: [1.05, 19.25]
Post Hoc
Factor VIII Inhibitor Risk Factor: Race
Number of treated participants who developed an inhibitor
Time frame: Duration of study which was to be at least 75 exposure days or 3 years (whichever came first)
Population: Immunogenicity Analysis Set- Participants who developed an inhibitor or who were inhibitor-free with ≥10 exposure days to rAHF-PFM
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| PUPs | Factor VIII Inhibitor Risk Factor: Race | Non-Caucasian | 8 Participants |
| PUPs | Factor VIII Inhibitor Risk Factor: Race | Caucasian | 26 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Race | Non-Caucasian | 9 Participants |
| PUPs -During On-Demand Treatment | Factor VIII Inhibitor Risk Factor: Race | Caucasian | 7 Participants |
95% CI: [1.18, 14.82]