Hemophilia A, Congenital
Conditions
Keywords
Factor VIII, von Willebrand Factor, Plasma-derived, Inhibitors, Immune tolerance induction (ITI), Antibodies, Hemophilia A
Brief summary
This is a multicenter, multinational, prospective, single-arm, nonrandomized, open-label study, planned in of approximately 25 male participants with congenital hemophilia A who will receive their first (primary) immune tolerance induction (ITI) treatment with alphanate. The study consists of 2 phases: * An ITI Treatment Phase in which all eligible participants will receive ITI treatment with alphanate for a period of up to 33 months. Upon confirmation of complete immune tolerization, participants will then enter a 12-month Prophylactic Phase. If, after 33 months of ITI, a participants has achieved partial immune tolerance, the participants will enter a 12-month Prophylactic Phase. * A 12-month Prophylactic Phase for all participants who meet the criteria for complete or partial success to continue on a prophylactic dosing regimen of alphanate. Due to limited enrollment, this study was early terminated.
Detailed description
Male participants \<12 years of age with an inhibitor titer \>0.6 to \<10 Bethesda Units (BU) will be screened before the planned start of ITI treatment. Participants continuing to meet the entrance criteria will enter the ITI Treatment Phase and receive daily doses of alphanate 100 IU/kg/day for up to 33 months, with a one-time option to increase to a dosing regimen of 200 IU/kg/day at any time after 90 days of ITI treatment. Participants will continue to receive their daily alphanate dose for up to 33 months until the titer is negative (\<0.6 BU) on 2 consecutive assessments and treatment success is confirmed by FVIII:C pharmacokinetic assessments, at which time they will enter the 12-month Prophylactic Phase. In addition, participants who have achieved partial immune tolerance at the completion of 33 months of ITI treatment will enter the 12-month Prophylactic Phase. Participants who do not achieve partial immune tolerance at the completion of 33 months of ITI treatment will be discontinued as treatment failures. The Prophylactic Phase begins with an 8-week taper period for participants tolerized with 100 IU/kg/day or with a 12-week taper period for participants tolerized with 200 IU/kg/day to bring the dose down in a step-wise manner to a prophylactic dose of alphanate 50 IU/kg every other day or 3 times per week, at the investigator's discretion. During the Prophylactic Phase, participants will be monitored monthly for the first 4 months and then every 2 months for the remaining 8 months to assess sustainability of immune tolerance. Due to limited enrollment, this study was early terminated.
Interventions
BIOLOGICALAlphanate
Bolus IV injection.
Sponsors
Grifols Biologicals, LLC
Grifols Therapeutics LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
No minimum to 12 Years
Healthy volunteers
No
Inclusion criteria
* The subject has a documented diagnosis of severe congenital hemophilia A with FVIII:C \<1% of normal. * The subject is a male \<12 years (and at least 2 years of age if in India) at the Baseline Visit. * The subject's documented historical peak inhibitor titer is ≥5 BU and ≤200 BU. * The subject has an inhibitor titer \>0.6 BU and \<10 BU at Screening. * The subject has had a delay ≤24 months from the date of diagnosis of the inhibitor to the start of the subject's ITI treatment.
Exclusion criteria
* The subject has acquired factor VIII (FVIII) deficiency. * The subject has previously received ITI treatment. * The subject has a recent (within 1 month) history of central line infection at the time of Screening. * The subject has a high risk of cardiovascular, cerebrovascular, or thromboembolic event as judged by the investigator. * The subject is currently undergoing treatment with immunosuppressive drugs (eg, systemic corticosteroids), azathioprine, cyclophosphamide, high dose immunoglobulin, interferon, or the use of a protein A column or plasmapheresis and is unwilling to discontinue these treatments starting at the screening visit. * The subject has a known infection with human immunodeficiency virus (HIV) or has clinical signs and symptoms consistent with current HIV infection. * The subject has a known previous infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) or has clinical signs and symptoms consistent with current HBV or HCV infection. * The subject has significant proteinuria, has a history of acute renal failure or severe renal impairment (blood urea nitrogen or creatinine \>2 times the upper limit of normal), or is receiving dialysis at Screening. * The subject has a value of aspartate transaminase or alanine aminotransferase \>2 times the upper limit of normal at Screening. * The subject has clinical evidence of any significant acute or chronic disease that, in the opinion of the investigator, may interfere with successful completion of the trial or place the subject at undue medical risk. * The subject has a history of anaphylaxis or severe systemic reaction to any plasma derived or other blood products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase | Up to 32.5 months | Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (\<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase | Up to 32.5 months | Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (\<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period. Partial immune tolerance was defined as participants achieving reduction of inhibitor titer to \<5 BU confirmed at 2 consecutive assessments within 2 weeks of each other, FVIII:C in vivo plasma recovery of \<66% of the predicted normal value or FVIII:C half-life of \<6 hours after a 72-hour FVIII treatment-free period and clinical response to FVIII therapy. |
| Percentage of Participants Who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase | 12 months during prophylactic phase | Relapse during the prophylactic phase for participants who have achieved complete immune tolerance was defined as a return of FVIII inhibitor titer to detectable levels (≥0.6 BU) or FVIII:C recovery \<66% of the predicted normal value or FVIII:C half-life \<6 hours, confirmed by repeat assessment within approximately 2 weeks. Relapse for participants who have achieved partial immune tolerance was defined as an increase of FVIII inhibitor titer to ≥5 BU, confirmed by repeat assessment within approximately 2 weeks. |
| Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase | Up to 32.5 months | Annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase |
Other
| Measure | Time frame | Description |
|---|---|---|
| Treatment-emergent Adverse Events | Up to 32.5 months | Incidence of treatment-emergent adverse events during the ITI Treatment Phase and Prophylactic Phase |
Countries
Canada, India, Italy, Russia, Spain, United States
Participant flow
Recruitment details
Participants took part in the study at two sites in India from 03 January 2018 (first participant enrolled to receive the study drug) to 18 September 2020 (last participant completed).
Pre-assignment details
Male participants with diagnosis of Congenital Hemophilia A were enrolled in a single arm to receive alphanate. The study was to be conducted in 2 phases: Immune Tolerance Induction Phase followed by Prophylactic Phase. However, due to the limited enrollment, the study was terminated prior to the start of Prophylactic Phase.
Participants by arm
| Arm | Count |
|---|---|
| Alphanate Participants entered the immune tolerance induction (ITI) phase and received alphanate IV at a starting dose of 100 IU/kg/day. Dose could be uptitrated to 200 IU/kg/day based on investigator's discretion. The maximum duration of treatment was 32 months and 2 weeks. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Treatment Failure | 1 |
Baseline characteristics
| Characteristic | Alphanate |
|---|---|
| Age, Categorical <=18 years | 2 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
Primary
Percentage of Participants Who Achieved Complete Immune Tolerance Within 33 Months of Initiation of Immune Tolerance Induction (ITI) Treatment Phase
Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (\<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period.
Time frame: Up to 32.5 months
Population: Data for this outcome measure was not collected and analysed, as the study was early terminated by the sponsor due to limited enrollment (non-safety related decision).
Secondary
Number of Bleeding Events During ITI Treatment Phase and Prophylactic Phase
Annualized frequencies of bleeding events during the ITI Treatment Phase and the Prophylactic Phase
Time frame: Up to 32.5 months
Population: This study was terminated, and the data is not reported for this outcome measure to maintain participant's confidentiality.
Secondary
Percentage of Participants Who Achieved Complete or Partial Immune Tolerance Without Relapse During the Prophylactic Phase
Relapse during the prophylactic phase for participants who have achieved complete immune tolerance was defined as a return of FVIII inhibitor titer to detectable levels (≥0.6 BU) or FVIII:C recovery \<66% of the predicted normal value or FVIII:C half-life \<6 hours, confirmed by repeat assessment within approximately 2 weeks. Relapse for participants who have achieved partial immune tolerance was defined as an increase of FVIII inhibitor titer to ≥5 BU, confirmed by repeat assessment within approximately 2 weeks.
Time frame: 12 months during prophylactic phase
Population: Data for this outcome measure was not collected and analysed, as the study was early terminated by the sponsor due to limited enrollment (non-safety related decision).
Secondary
Percentage of Participants Who Achieved Either Complete or Partial Immune Tolerance Within 33 Months of Initiation of ITI Treatment Phase
Complete immune tolerance was defined as the participants achieving 2 consecutive undetectable inhibitor titers (\<0.6 BU) performed within 2 weeks of each other, Factor VIII activity (FVIII:C) in vivo plasma recovery ≥66% of the predicted normal value and FVIII:C half-life ≥6 hours after a 72-hour FVIII treatment-free period. Partial immune tolerance was defined as participants achieving reduction of inhibitor titer to \<5 BU confirmed at 2 consecutive assessments within 2 weeks of each other, FVIII:C in vivo plasma recovery of \<66% of the predicted normal value or FVIII:C half-life of \<6 hours after a 72-hour FVIII treatment-free period and clinical response to FVIII therapy.
Time frame: Up to 32.5 months
Population: Data for this outcome measure was not collected and analysed, as the study was early terminated by the sponsor due to limited enrollment (non-safety related decision).
Other Pre-specified
Treatment-emergent Adverse Events
Incidence of treatment-emergent adverse events during the ITI Treatment Phase and Prophylactic Phase
Time frame: Up to 32.5 months