Hemophilia A
Conditions
Keywords
Hemophilia A, Factor VIII inhibitors, vWF/FVIII, rFVIII
Brief summary
The primary objective of the study is to assess the immunogenicity of VWF/FVIII and of rFVIII concentrates by determining the frequency of inhibitor development in previously untreated patients (PUPs) or minimally blood component-treated (MBCTPs) in the first 50 EDs or in the first 3 years from enrollment, whichever occurs first. .
Detailed description
Patients meeting the enrollment criteria will be consecutively enrolled at each participating centre, randomized to be treated exclusively with a single FVIII product either plasma-derived or recombinant, and followed up until inhibitor development or until 50 exposure days (EDs) or 3 years from enrolment have elapsed, whichever comes first. Study products, belonging to the class of rFVIII concentrates and to the class of plasma-derived VWF/FVIII concentrates, will be provided for free to the patients for all the duration of the study
Interventions
DRUGPLASMA DERIVED Factor VIII
Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
DRUGRecombinant FVIII
Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding
Sponsors
Sintesi Research Srl
Fondazione Angelo Bianchi Bonomi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
1 Minutes to 6 Years
Healthy volunteers
No
Inclusion criteria
* Male subjects * Any ethnicity * Age \<6 years * Severe haemophilia A (FVIII:C \<1%), as confirmed at enrolment by the central laboratory. o Those patients diagnosed locally as severe but subsequently found to have FVIII levels \>= 1% on testing at the central laboratory will be separately recorded in the screening list. * Previously untreated (0 EDs to any FVIII concentrates or blood products) or minimally treated (\<5 EDs) with blood components, namely whole blood, fresh frozen plasma, packed red blood cells, platelets or cryoprecipitate. o Patients not meeting these criteria will be separately recorded in the screening list. * Negative inhibitor measurement at both local and central laboratory at screening * Ability to comply with study requirements * Signed informed consent of legal tutors o Patients who will not accept to enter into the study or to be randomized will be separately recorded.
Exclusion criteria
* Previous history of FVIII inhibitor * Other congenital or acquired bleeding defects * Plasma FVIII level \>= 1%, as assayed at the central laboratory o Those patients originally diagnosed locally as severe but subsequently found to have FVIII levels ranging from 1% to 2% on testing at the central laboratory will be separately recorded in the screening list. * Concomitant congenital or acquired immunodeficiency * Concomitant treatment with systemic immunosuppressive drugs * Concomitant treatment with any investigational drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Evaluate the Frequency of Transient Inhibitors | In the 6 months after inhibitor development | Number of participants for each group who developed transient inhibitors (this means, those inhibitors which disappeared spontaneously within 6 months without immunotolerance treatment). |
| To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs) | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | Number of EDs: Number of Exposure Days (EDs) after which the inhibitors develop |
| To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset) | During 6 months of observation, from the inhibitor occurrence | Inhibitor Titre at Onset |
| To Evaluate the Anamnestic Response of Inhibitor Patients | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | — |
| To Evaluate Laboratory Factors Potentially Associated to Inhibitor Development | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | — |
| To Evaluate the Incidence of All Other Adverse Events Related and Not Related to the Products Used | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | — |
| To Evaluate Clinical Factors Potentially Associated to Inhibitor Development | During the first 50 exposure days or first 3 years of enrollment, whichever occurs first | — |
Countries
Argentina, Austria, Brazil, Chile, Egypt, India, Iran, Italy, Mexico, Saudi Arabia, South Africa, Spain, Turkey (Türkiye), United States
Participant flow
Recruitment details
303 boys were assessed for eligibility, 39 were excluded, therefore, of those 303, only 264 patients underwent randomization. Of these 264, only 251 were analyzed.
Participants by arm
| Arm | Count |
|---|---|
| pd vWF/FVIII Plasma-derived vWF/FVIII
PLASMA DERIVED Factor VIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding | 125 |
| rFVIII Recombinant FVIII
Recombinant FVIII: Maximum dosage : 50IU per kilo. 2-3 times per week or on demand during acute episode of bleeding | 126 |
| Total | 251 |
Baseline characteristics
| Characteristic | pd vWF/FVIII | Total | rFVIII |
|---|---|---|---|
| Age, Continuous | 19.1 months STANDARD_DEVIATION 14.3 | 20.2 months STANDARD_DEVIATION 21.68 | 21.3 months STANDARD_DEVIATION 16.3 |
| Mutation Status Non-null mutation | 16 participants | 37 participants | 21 participants |
| Mutation Status Null mutation | 101 participants | 197 participants | 96 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 41 Participants | 84 Participants | 43 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants | 7 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 40 Participants | 76 Participants | 36 Participants |
| Race (NIH/OMB) White | 39 Participants | 84 Participants | 45 Participants |
| Region of Enrollment Argentina | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Austria | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Brazil | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Chile | 1 participants | 4 participants | 3 participants |
| Region of Enrollment Egypt | 38 participants | 75 participants | 37 participants |
| Region of Enrollment India | 40 participants | 83 participants | 43 participants |
| Region of Enrollment Iran | 14 participants | 32 participants | 18 participants |
| Region of Enrollment Italy | 5 participants | 9 participants | 4 participants |
| Region of Enrollment Mexico | 4 participants | 6 participants | 2 participants |
| Region of Enrollment Saudi Arabia | 1 participants | 1 participants | 0 participants |
| Region of Enrollment South Africa | 2 participants | 4 participants | 2 participants |
| Region of Enrollment Spain | 3 participants | 6 participants | 3 participants |
| Region of Enrollment Turkey | 2 participants | 3 participants | 1 participants |
| Region of Enrollment United States | 9 participants | 18 participants | 9 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 125 Participants | 251 Participants | 126 Participants |
| Treatment Regimen Modified prophylaxis | 43 participants | 94 participants | 51 participants |
| Treatment Regimen On-demand | 61 participants | 117 participants | 56 participants |
| Treatment Regimen Standard prophylaxis | 21 participants | 40 participants | 19 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 95 / 133 | 86 / 131 |
| serious Total, serious adverse events | 20 / 133 | 13 / 131 |
Outcome results
Primary
To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs
Expressed with the numebr of patients for each group who developed FVIII inhibitors. PUPs: Previously Untreated Patients MBCTPs: Minimally Blood Component-Treated Patients
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| pd vWF/FVIII | To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs | 29 participants |
| rFVIII | To Assess the Immunogenicity of Plasma Derived VWF/FVIII and rFVIII Concentrates by Determining the Frequency of Inhibitor Development in the First 50 EDs or in the First 3 Years From Enrolment, Whichever Comes First in PUPs and MBCTs | 47 participants |
Secondary
To Evaluate Clinical Factors Potentially Associated to Inhibitor Development
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Population: Data were not collected and the Outcome will never be analyzed
Secondary
To Evaluate Laboratory Factors Potentially Associated to Inhibitor Development
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Population: Data were not collected and the Outcome will never be analyzed
Secondary
To Evaluate the Anamnestic Response of Inhibitor Patients
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Population: Data were not collected and the Outcome will never be analyzed.
Secondary
To Evaluate the Frequency of Transient Inhibitors
Number of participants for each group who developed transient inhibitors (this means, those inhibitors which disappeared spontaneously within 6 months without immunotolerance treatment).
Time frame: In the 6 months after inhibitor development
Population: Data at 6-month follow-up were missing for two patients assigned to plasma- derived factor VIII and three patients assigned to recombinant factor VIII.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| pd vWF/FVIII | To Evaluate the Frequency of Transient Inhibitors | 7 participants |
| rFVIII | To Evaluate the Frequency of Transient Inhibitors | 12 participants |
Secondary
To Evaluate the Incidence of All Other Adverse Events Related and Not Related to the Products Used
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
Population: Data were not collected and the Outcome will never be analyzed
Secondary
To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs)
Number of EDs: Number of Exposure Days (EDs) after which the inhibitors develop
Time frame: During the first 50 exposure days or first 3 years of enrollment, whichever occurs first
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| pd vWF/FVIII | To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs) | 8 Exposure days |
| rFVIII | To Evaluate the Modality of Occurrence of Inhibitors (Number of EDs) | 8 Exposure days |
Secondary
To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset)
Inhibitor Titre at Onset
Time frame: During 6 months of observation, from the inhibitor occurrence
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| pd vWF/FVIII | To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset) | 12 Bethesda Units |
| rFVIII | To Evaluate the Modality of Occurrence of Inhibitors (Titre at Onset) | 16.3 Bethesda Units |