Hemophilia A or B With Inhibitors
Conditions
Brief summary
The purpose of this study is to: * 1\. To evaluate the tolerability and safety of infusing reduced volume Factor Eight Inhibitor Bypassing Activity (FEIBA) at the standard infusion rate of 2 U/kg/min * 2\. To evaluate the tolerability and safety of infusing reduced volume FEIBA at increased rates of 4 and 10 U/kg/min, in comparison to the standard rate of 2 U/kg/min at the regular volume
Detailed description
15 JUN 2020: The temporary enrollment stop of new patients into this study due to the COVID-19 pandemic has been lifted in one or more countries/sites, and the study is now again enrolling new patients. However, some countries/sites may still have paused the enrollment of new patients due to the pandemic. 23 APRIL 2020: Enrollment of new patients into this study has been paused due to the COVID-19 situation. The duration of this pause is dependent on the leveling and control of the COVID-19 pandemic.
Interventions
BIOLOGICALFEIBA
Anti-inhibitor Coagulant Complex Nanofiltered (activated prothrombin complex concentrate \[APCC\]), FEIBA NF.
Sponsors
Baxalta Innovations GmbH, now part of Shire
Baxalta now part of Shire
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Greater than or equal to (\> or =) 18 to less than or equal to (\< or =) 65 years old at the time of screening. 2. Hemophilia A or B of any severity, with a documented \> or = 3 months history of inhibitors (\> or = 0.6 Bethesda units \[BU\]) requiring the use of bypassing agents (FEIBA or rFVIIa) prior to screening. Inhibitor level will be tested at screening if no documented history is available. 3. Hepatitis C virus (HCV) negative, either by antibody testing or polymerase chain reaction (PCR); or HCV positive with stable liver disease. 4. Human immune deficiency virus (HIV) negative; or HIV positive with stable disease and CD4 count \> or = 200 cells per cubic millimetre (cell/mm3) at screening. 5. Adequate venous access. 6. Willing and able to comply with the requirements of the protocol. 7. If a female of childbearing potential, must have a negative blood pregnancy test and agrees to employ adequate birth control measures for the duration of the study, such as: a. Abstain from sexual intercourse, b. Use a reliable method of contraception (contraception such as an intrauterine device, barrier method \[e.g., diaphragm or sponge; female condom not permitted\] with spermicide, oral contraceptive, injectable progesterone, sub dermal implant), and have their male partner use a condom 8. If female of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria: 1. Postmenopausal, defined as amenorrhea for at least 12 months following cessation of all exogenous hormonal treatments and with follicle-stimulating hormone levels within the laboratory-defined postmenopausal range or postmenopausal with amenorrhea for at least 24 months and on hormonal replacement therapy. 2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, bilateral tubal ligation (with no subsequent pregnancy at least 1 year from bilateral tubal ligation), or bilateral salpingectomy.
Exclusion criteria
1. Known hypersensitivity to FEIBA or any of its components. 2. Advanced liver disease (e.g., liver biopsy confirmed diagnosis of cirrhosis, portal vein hypertension, ascites, prothrombin time \[PT\] 5 seconds above upper limit of normal). 3. Planned elective surgery during participation in this study (excluding minor procedures that will not need preventative bleeding treatments, such as exchanges of peripherally inserted central catheters). 4. Platelet count less than (\<) 100,000/ microliter (μL). 5. Taking Emicizumab (Hemlibra) for bleed prevention. 6. Clinical or laboratory evidence of disseminated intravascular coagulation based on medical history. 7. Prior history or evidence of thromboembolic event: acute myocardial infarction, deep vein thrombosis, pulmonary embolism, etc. 8. Diagnosis of advanced atherosclerosis, malignancy, and/or other diseases that may increase the participant's risk of thromboembolic complications. 9. Participant is taking any immunomodulating drug (e.g., corticosteroid agents at a dose equivalent to hydrocortisone greater than (\>) 10 milligram per day (mg/day), or α-interferon) within 30 days prior to enrollment except anti-retroviral chemotherapy. 10. Herbal supplements that contain anti-platelet activity. 11. Participant has participated in another clinical study involving an investigational product (IP) or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an IP or investigational device during the course of this study. 12. Participant is a family member or employee of the investigator. 13. Clinically significant medical, psychiatric or cognitive illness, or recreational drug/alcohol use that, in the opinion of the investigator, would affect participant safety or compliance.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Any Treatment Emergent Adverse Event (TEAE) | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. |
| Number of Participants With Any Hypersensitivity Reaction | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | Number of participants with AEs particular to allergic-type hypersensitivity reactions were assessed. Clinical manifestations of hypersensitivity reactions included, but was not limited to skin rash, pruritus (itching), urticaria (hives), angioedema (for example, swelling of the lips and/or tongue) and anaphylactic reaction. |
| Number of Participants With Any Thromboembolic Event | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | Participants with adverse events related to thromboembolic event were reported. Clinical manifestations of thromboembolic events included, but was not limited to myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and transitory ischemic attack. |
| Number of Participants With Any Infusion Site Reaction | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | Infusion sites were monitored for pain, tenderness, erythema, and swelling. Infusion site evaluations were made by clinical staff or by the participant or caregiver. |
| Number of Participants With AEs Leading to Study Discontinuation | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | — |
| Number of Participants With Vital Signs Considered as AEs | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | Number of participants with vital signs considered as AEs were assessed. Vital signs included body temperature (degree Celsius or degrees Fahrenheit \[°C or °F\]), respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure (millimeter of mercury \[mmHg\]). |
| Number of Participants With Laboratory Assessments Considered as AEs | From first dose of study drug up to 7 days after the end of infusion (up to Day 41) | Number of participants with Laboratory Assessments considered as AEs were assessed. Laboratory assessments included hematology, clinical chemistry, coagulation testing, serological testing, pregnancy testing, cluster differentiation 4 (CD4). |
Countries
Croatia, North Macedonia, Ukraine
Participant flow
Recruitment details
Participants took part in the study at 18 investigative sites in Thailand, Malaysia, Algeria, Croatia, India, Poland, Turkey, and Ukraine from 12 February 2019 to 27 December 2021. Participants with a diagnosis of Congenital Hemophilia A were enrolled.
Pre-assignment details
Participants received factor eight inhibitor bypassing activity (FEIBA) reconstituted in regular volume and FEIBA reconstituted in 50% reduced volume in a crossover fashion for Part 1 and FEIBA reconstituted in 50% reduced volume at escalated infusion rates for Part 2. Participants who completed Part 1 entered Part 2 of the study. A total of 45 participants were enrolled in the study out of which 33 participants received the study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Part 1 + Part 2: Overall FEIBA Treatment Part 1:
Participants who were eligible were randomized to receive: 3 infusions (infusions 1, 2 and 3) of FEIBA 85 ± 15 U/kg, reconstituted in regular volume SWFI followed by 3 infusions (infusions 4, 5 and 6) of FEIBA 85 ± 15 U/kg reconstituted in 50% reduced volume SWFI (Sequence A) or: 3 infusions (infusions 1, 2 and 3) of FEIBA 85 ± 15 U/kg, reconstituted in 50% reduced volume SWFI, followed by 3 infusions of FEIBA 85 ± 15 U/kg, reconstituted in regular volume SWFI (Sequence B).
All infusions in Part 1 were given at the standard infusion rate of 2 U/kg/min.
Part 2:
Participants who completed Part 1, received FEIBA 85 ± 15 U/kg, reconstituted in 50% reduced volume SWFI at an increased rate of 4 U/kg/min for infusions 7, 8, and 9, followed by FEIBA 85 ± 15 U/kg, reconstituted in 50% reduced volume SWFI at an increased rate of 10 U/kg/min for infusions 10, 11, and 12. | 33 |
| Total | 33 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Part 1: Day 1 up to Day 16 | Adverse Event | 2 | 0 |
| Part 1: Day 1 up to Day 16 | Withdrawal by Subject | 1 | 0 |
| Part 2: Day 19 up to Day 41 | Adverse Event | 1 | 0 |
| Part 2: Day 19 up to Day 41 | Physician Decision | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1 + Part 2: Overall FEIBA Treatment |
|---|---|
| Age, Continuous | 35.4 years STANDARD_DEVIATION 11.92 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 31 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 17 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 | 16 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 30 | 0 / 30 | 0 / 28 |
| other Total, other adverse events | 2 / 33 | 5 / 30 | 0 / 30 | 2 / 28 |
| serious Total, serious adverse events | 3 / 33 | 1 / 30 | 0 / 30 | 0 / 28 |
Outcome results
Primary
Number of Participants With AEs Leading to Study Discontinuation
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With AEs Leading to Study Discontinuation | 2 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With AEs Leading to Study Discontinuation | 1 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With AEs Leading to Study Discontinuation | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With AEs Leading to Study Discontinuation | 0 Participants |
Primary
Number of Participants With Any Hypersensitivity Reaction
Number of participants with AEs particular to allergic-type hypersensitivity reactions were assessed. Clinical manifestations of hypersensitivity reactions included, but was not limited to skin rash, pruritus (itching), urticaria (hives), angioedema (for example, swelling of the lips and/or tongue) and anaphylactic reaction.
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Any Hypersensitivity Reaction | 3 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Any Hypersensitivity Reaction | 1 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Any Hypersensitivity Reaction | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Any Hypersensitivity Reaction | 0 Participants |
Primary
Number of Participants With Any Infusion Site Reaction
Infusion sites were monitored for pain, tenderness, erythema, and swelling. Infusion site evaluations were made by clinical staff or by the participant or caregiver.
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Any Infusion Site Reaction | 2 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Any Infusion Site Reaction | 1 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Any Infusion Site Reaction | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Any Infusion Site Reaction | 0 Participants |
Primary
Number of Participants With Any Thromboembolic Event
Participants with adverse events related to thromboembolic event were reported. Clinical manifestations of thromboembolic events included, but was not limited to myocardial infarction, deep vein thrombosis, pulmonary embolism, stroke and transitory ischemic attack.
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Any Thromboembolic Event | 0 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Any Thromboembolic Event | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Any Thromboembolic Event | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Any Thromboembolic Event | 0 Participants |
Primary
Number of Participants With Any Treatment Emergent Adverse Event (TEAE)
An adverse event (AE) is any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment.
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Any Treatment Emergent Adverse Event (TEAE) | 8 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Any Treatment Emergent Adverse Event (TEAE) | 7 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Any Treatment Emergent Adverse Event (TEAE) | 1 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Any Treatment Emergent Adverse Event (TEAE) | 4 Participants |
Primary
Number of Participants With Laboratory Assessments Considered as AEs
Number of participants with Laboratory Assessments considered as AEs were assessed. Laboratory assessments included hematology, clinical chemistry, coagulation testing, serological testing, pregnancy testing, cluster differentiation 4 (CD4).
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA). Participants were counted more than once in the arm groups. Participants counted in Part 1 regular volume and in Part 1 reduced volume were the same.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Laboratory Assessments Considered as AEs | 2 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Laboratory Assessments Considered as AEs | 2 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Laboratory Assessments Considered as AEs | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Laboratory Assessments Considered as AEs | 0 Participants |
Primary
Number of Participants With Vital Signs Considered as AEs
Number of participants with vital signs considered as AEs were assessed. Vital signs included body temperature (degree Celsius or degrees Fahrenheit \[°C or °F\]), respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure (millimeter of mercury \[mmHg\]).
Time frame: From first dose of study drug up to 7 days after the end of infusion (up to Day 41)
Population: SAS included all participants who received at least one dose of IP (i.e., FEIBA).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1:FEIBA 85 ± 15 U/kg Regular Volume at 2 U/kg/Min Rate | Number of Participants With Vital Signs Considered as AEs | 0 Participants |
| Part 1:FEIBA 85±15 U/kg 50% Reduced Volume at 2 U/kg/Min Rate | Number of Participants With Vital Signs Considered as AEs | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 4 U/kg/Min Rate | Number of Participants With Vital Signs Considered as AEs | 0 Participants |
| Part 2:FEIBA 85±15 U/kg 50% Reduced Volume at 10 U/kg/Min Rate | Number of Participants With Vital Signs Considered as AEs | 1 Participants |