Hemophilia A
Conditions
Keywords
ITI, rFVIIIFc, Immune Tolerance Induction
Brief summary
The primary purpose of this study is to describe the outcome of Immune Tolerance Induction (ITI) treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients with haemophilia A who have failed previous attempts at tolerization.
Detailed description
This is an open-label, single-arm, interventional multi-center study designed to explore ITI performed with recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc) within a timeframe of 60 weeks in patients with severe haemophilia A, who have failed previous attempts at tolerization including use of immunosuppressants.
Interventions
BIOLOGICALRecombinant coagulation factor (rFVIIIFc)
rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement administered intravenously.
Sponsors
Bioverativ Therapeutics Inc.
Swedish Orphan Biovitrum
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Healthy volunteers
No
Inclusion criteria
1. Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations 2. Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record 3. Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII 4. Diagnosed with high titer inhibitors (historical peak ≥5 Bethesda units (BU)/mL according to medical records) 5. Inhibitor titer \>0.6 BU at screening 6. Failed previous ITI attempt(s) with any plasma-derived or recombinant conventional or extended half-life FVIII including the use of immunosuppressant The attempt should be documented in the medical records and have the following characteristics: * A minimum FVIII dose equivalent to the low dose arm of the International ITI study (50 IU/kg, 3 times/week) * A minimum ITI treatment period of 33 months or * Shorter than 33 months if no downward trend of at least 20% in the inhibitor titer in a 6-month period after the initial 3 months of the ITI treatment 7. All patients must practice effective contraception during the study and for 3 months after their last dose of study treatment
Exclusion criteria
1. Other coagulation disorder(s) in addition to haemophilia A 2. History of hypersensitivity reactions associated with any rFVIIIFc administration 3. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator 4. Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed. 5. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of Hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids 6. Abnormal renal function (serum creatinine \>2.0 mg/dL) as assessed by local lab 7. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>5 × upper limit of normal (ULN) as assessed by local lab 8. Serum total bilirubin \>3 × ULN as assessed by local lab 9. Cluster of differentiation 4 (CD4) lymphocytes ≤200 mm3 if known as HIV antibody positive at Screening 10. Viral load of ≥400 copies/mL if known HIV antibody positive at Screening 11. Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization 12. Previous inclusion in this study 13. Participation in another concurrent clinical interventional study within 30 days of screening or intake of an investigational drug within five half-lives of that investigational drug has passed 14. Foreseeable inability to cooperate with given instructions or study procedures 15. Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient's ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with rFVIIIFc
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ITI Success | up to 60 weeks | Number of patients who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: * Negative titer for inhibitor (\<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits * FVIII incremental recovery (IR) \>66% of the expected IR at 2 consecutive visits * FVIII half-life (t½) ≥7 hours |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment | Up to 48 weeks | Relapse was defined as a positive inhibitor (≥0.6 BU/mL) on 2 consecutive assessments and incremental recovery ≤66 % of the expected incremental recovery on 2 consecutive assessments |
| Number of Bleedings During ITI Treatment | up to 60 weeks | Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode. |
| Bleeding Rate During a 48-week Period Following Successful ITI Treatment | up to 48 weeks | Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode. |
| Adverse Events (AEs) | SAEs - approx 166 weeks AEs - approx 110 weeks | All observed adverse events as a measure of tolerability. (AE=adverse event, SAE=serious adverse event, TEAE=treatment emergent adverse event) |
| Consumption of rFVIIIFc | Up to 60 weeks | Consumption will be assessed based on amount of administered study treatment during the ITI period. |
| Time to ITI Success | up to 60 weeks | Time to the patient reaches ITI success according to the pre-defined criteria For the subset of patients who were classified as partial success at the end of the ITI period, the time to fulfillment of the criteria for partial success was also analyzed descriptively. |
| Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment | up to 48 weeks | Days missed school or work will be registered by the patients in an electronic diary |
| Number of Hospitalizations During ITI Treatment | up to 60 weeks | Days of hospitalization will be collected by the Investigator at the study visits |
| Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment | Up to 48 weeks | Days of hospitalization will be collected by the Investigator at the study visits |
| Adherence | up to 108 weeks | Defined as percentage of administered doses versus planned doses |
| Number of Days Missed School or Work During ITI Treatment | up to 60 weeks | Days missed school or work will be registered by the patients in an electronic diary |
Countries
Canada, Germany, Ireland, Slovenia, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Recruitment was open at 18 sites in 9 countries in Northern America and Europe. 11 sites in 7 countries recruited patients. It was initially planned to enroll 20 patients but due to recruitment challenges and a changing treatment landscape the recruitment was stopped after enrolling 16 patients. Recruitment was open from Aug 2017 to Nov 2019. 18 patients were screened and 16 enrolled into this study.
Pre-assignment details
After informed consent was provided, patients underwent study specific screening procedures. During the 4- to 6-week screening period, patients continued with their usual treatment regimen in accordance with the local standard of care. Patients who met all inclusion and no exclusion criteria specified by the protocol were enrolled into the study. The 2 screening failures did not meet inclusion criteria 1 (signed informed consent) and 5 (inhibitor titer ≥0.6 BU at screening) respectively.
Participants by arm
| Arm | Count |
|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) Participants will receive rFVIIIFc at a dose of 200 international units (IU)/kilogram (kg) as once daily injections or divided on several injections per day at the discretion of the Investigator, starting at baseline visit up to maximum of 60 Weeks during the ITI Period. Participants who meet the criteria for ITI success will enter a tapering period of 16 weeks where the dose will be tapered down until a prophylactic dose, as judged by the Investigator, is achieved and thereafter a follow-up period of 32 weeks where the patient will continue to receive prophylactic treatment with rFVIIIFc.
Recombinant coagulation factor (rFVIIIFc): rFVIIIFc 200 IU/kg/day during ITI Period and thereafter adjusted according to the Investigator's judgement
administered intravenously. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 2 |
| Overall Study | Other | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Recombinant Coagulation Factor VIII Fc (rFVIIIFc) |
|---|---|
| Age, Categorical <=18 years | 15 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 7.5 years |
| Hemophilia history - Family history of Inhibitors No | 5 Participants |
| Hemophilia history - Family history of Inhibitors Unknown | 4 Participants |
| Hemophilia history - Family history of Inhibitors Yes | 7 Participants |
| Hemophilia history - severity Mild | 0 Participants |
| Hemophilia history - severity Moderate | 0 Participants |
| Hemophilia history - severity Severe | 16 Participants |
| Inhibitor history - Age at Inhibitor development | 1.9 years STANDARD_DEVIATION 3.6 |
| Inhibitor History - Historical Peak Titre Level | 127.4 BU/ml |
| Number of previous ITI Treatments 1 Treatment | 10 Participants |
| Number of previous ITI Treatments 2 Treatments | 4 Participants |
| Number of previous ITI Treatments 3 Treatments | 2 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 1 Participants |
| Race/Ethnicity, Customized Race White | 15 Participants |
| Region of Enrollment Canada | 3 participants |
| Region of Enrollment Germany | 4 participants |
| Region of Enrollment Ireland | 3 participants |
| Region of Enrollment Slovenia | 1 participants |
| Region of Enrollment Sweden | 1 participants |
| Region of Enrollment United Kingdom | 3 participants |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 16 / 16 |
| serious Total, serious adverse events | 7 / 16 |
Outcome results
Primary
ITI Success
Number of patients who achieve ITI success where ITI success is defined as achieving all 3 of the following criteria: * Negative titer for inhibitor (\<0.6 Bethesda units/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits * FVIII incremental recovery (IR) \>66% of the expected IR at 2 consecutive visits * FVIII half-life (t½) ≥7 hours
Time frame: up to 60 weeks
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | ITI Success | ITI success | 1 Participants |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | ITI Success | Partial Success | 2 Participants |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | ITI Success | ITI failure | 6 Participants |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | ITI Success | Not determinable due to withdrawal during the ITI | 7 Participants |
Secondary
Adherence
Defined as percentage of administered doses versus planned doses
Time frame: up to 108 weeks
Population: 16 patients analyzed for the ITI period. 1 patient analyzed for the tapering and follow-up period (1 patient achieved ITI success and entered tapering and follow-up periods).
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adherence | ITI period | 92.52 % of administered vs planned doses | Standard Deviation 13.86 |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adherence | Tapering period | 100.5 % of administered vs planned doses | Standard Deviation 0 |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adherence | Follow-up period | 98.56 % of administered vs planned doses | Standard Deviation 0 |
Secondary
Adverse Events (AEs)
All observed adverse events as a measure of tolerability. (AE=adverse event, SAE=serious adverse event, TEAE=treatment emergent adverse event)
Time frame: SAEs - approx 166 weeks AEs - approx 110 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | TEAEs | 188 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Serious AEs | 21 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Serious TEAEs | 18 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Non-serious TEAEs | 170 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Related TEAEs | 2 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Mild AEs | 145 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Moderate AEs | 42 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | Severe AEs | 4 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | AEs Leading to Withdrawal | 3 events |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Adverse Events (AEs) | AEs Leading to Death | 0 events |
Secondary
Bleeding Rate During a 48-week Period Following Successful ITI Treatment
Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode.
Time frame: up to 48 weeks
Population: Only patients achieving ITI success are included in the analysis for this endpoint. 1 patient achieved ITI success.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Bleeding Rate During a 48-week Period Following Successful ITI Treatment | 5.07 Annualized bleeding rate(bleedings/year) |
Secondary
Consumption of rFVIIIFc
Consumption will be assessed based on amount of administered study treatment during the ITI period.
Time frame: Up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Consumption of rFVIIIFc | 62586.7 IU/kg |
Secondary
Consumption of rFVIIIFc
Consumption will be assessed based on amount of administered study treatment during the ITI period.
Time frame: Up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Consumption of rFVIIIFc | 1902625.0 IU |
Secondary
Number of Bleedings During ITI Treatment
Only bleeds requiring treatment with rFVIIIFc or bypassing agents should be registered. A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the last injection of bypassing agents or rFVIIIFc to treat the bleeding episode.
Time frame: up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Bleedings During ITI Treatment | 4.70 Annualized bleeding rate(bleedings/year) |
Secondary
Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment
Days missed school or work will be registered by the patients in an electronic diary
Time frame: up to 48 weeks
Population: Only patients achieving ITI success are included in the analysis for this endpoint. 1 patient achieved ITI success.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Days Missed School or Work During a 48-week Period Following Successful ITI Treatment | 0 Days |
Secondary
Number of Days Missed School or Work During ITI Treatment
Days missed school or work will be registered by the patients in an electronic diary
Time frame: up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Days Missed School or Work During ITI Treatment | 0.5 Days/year |
Secondary
Number of Days Missed School or Work During ITI Treatment
Days missed school or work will be registered by the patients in an electronic diary
Time frame: up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Days Missed School or Work During ITI Treatment | 0.5 Days |
Secondary
Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment
Days of hospitalization will be collected by the Investigator at the study visits
Time frame: Up to 48 weeks
Population: Only patients achieving ITI success are included in the analysis for this endpoint. 1 patient achieved ITI success.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Hospitalizations During a 48-week Period Following Successful ITI Treatment | 0 Days |
Secondary
Number of Hospitalizations During ITI Treatment
Days of hospitalization will be collected by the Investigator at the study visits
Time frame: up to 60 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Number of Hospitalizations During ITI Treatment | 0 Days |
Secondary
Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment
Relapse was defined as a positive inhibitor (≥0.6 BU/mL) on 2 consecutive assessments and incremental recovery ≤66 % of the expected incremental recovery on 2 consecutive assessments
Time frame: Up to 48 weeks
Population: Only patients achieving ITI success are included in the analysis for this endpoint. 1 patient achieved ITI success.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Occurrence of Relapse During a 48-week Period Following Successful ITI Treatment | 0 Participants |
Secondary
Time to ITI Success
Time to the patient reaches ITI success according to the pre-defined criteria For the subset of patients who were classified as partial success at the end of the ITI period, the time to fulfillment of the criteria for partial success was also analyzed descriptively.
Time frame: up to 60 weeks
Population: 1 patient achieved ITI success and 2 patients achieved partial success
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Time to ITI Success | Time to ITI success | 46.71 weeks | Standard Deviation 0 |
| Recombinant Coagulation Factor VIII Fc (rFVIIIFc) | Time to ITI Success | Time to Partial Success | 38.76 weeks | Standard Deviation 15.05 |