Haemophilic Pseudotumour
Conditions
Brief summary
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of hemophilia A patients (baseline FVIII level \<40%) with and without inhibitors with hemophilic pseudotumors; secondary outcomes will assess changes in quality of life and activity level in treated patients.
Detailed description
This is a single arm, phase 4, prospective, open-label, United States single-center study to assess the hemostatic efficacy and safety of Hemlibra (emicizumab) for hemostatic control of hemophilia A patients, (baseline FVIII level \<40%), children and adults, with and without inhibitors with hemophilic pseudotumors; secondary outcomes will assess changes in quality of life and activity level in treated patients. Hemlibra (emicizumab) will be administered as primary weekly prophylaxis after the enrollment/screening visit is complete (approximately 7-10 days after screening, if laboratory results are available and eligibility is confirmed). If an activity monitoring device is typically utilized by the patient (eg, a Fitbit) then permission will be requested from the patient at screening to access the data for 1 month prior to screening as a baseline comparator for post-treatment activity. The use of an activity-monitoring device is not required by the study. The enrollment period is 2 years and the study will last a maximum of 4 years; subjects will receive study medication (Hemlibra, emicizumab) for a minimum of 2 years and a maximum of 4 years based upon time of enrollment. Hemlibra (emicizumab) will be administered using the FDA-approved once-weekly dosing regimen for loading dose and prophylactic dose. Breakthrough bleeding events will be recorded and treated with locally available FVIII (eg, pdFVIII or rFVIII) in non-inhibitor subjects and inhibitor subjects with low titer inhibitors (titer\<5 BU). The lowest dose of FVIII expected to achieve hemostasis will be utilized for treatment of breakthrough bleeding events in non-inhibitor and low-titer inhibitor patients. Subjects with high-titer inhibitors (titer ≥5 BU) and those with low titer inhibitors who do not respond to FVIII will be required to utilize rFVIIa as first line therapy; aPCC (\<100 U/kg/day for preferably no more than 1 day) may only be used upon approval of the Study Investigator and under the supervision of a physician. The proposed study is seeking to address the following knowledge gaps: Does weekly prophylactic Hemlibra (emicizumab) reduce the rate of bleeding events in subjects with hemophilia A and pseudotumor, including the rate of hospitalization, anemia and transfusion? Does weekly prophylactic Hemlibra (emicizumab) control the progression of hemophilic pseudotumor? Does weekly prophylactic Hemlibra (emicizumab) result in an increase in QoL and activity level?
Interventions
DRUGEmicizumab
bispecific monoclonal antibody binding to activated Factor IX and Factor X
Sponsors
Genentech, Inc.
Indiana Hemophilia &Thrombosis Center, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single arm prospective open-label single-center study
Eligibility
Sex/Gender
ALL
Healthy volunteers
No
Inclusion criteria
* Signed informed consent form from the subject, parent or guardian * Diagnosis of congenital hemophilia A (baseline FVIII level \<40%) with or without FVIII inhibitor, either high or low responding, regardless of titer * Diagnosis of a hemophilic pseudotumor confirmed by radiologic assessment such as CT or MRI * Any weight or BMI * Medical documentation of prophylactic or episodic treatment (FVIII or bypassing agent) and the number of bleeding episodes for at least 16 weeks, and up to 6 months if available, prior to entry into the study * Medical documentation of any need for PRBC transfusion or hospitalization for 6 months prior to entry into the study * Subjects with a history of an inhibitor should provide documentation of the inhibitor history including date of initial diagnosis of inhibitor, peak titer, and agent utilized for hemostatic control * Subjects with high titer inhibitors or those with low titer inhibitors who do not respond to FVIII must be willing to use rFVIIa as first line therapy for the treatment of breakthrough bleeding events * Medical documentation of ITI therapy for subjects with a history of a FVIII inhibitor and ITI, including current FVIII inhibitor titer * Willingness to discontinue any current prophylactic hemostatic regimen (FVIII or bypassing agent) and/or FVIII ITI therapy for the duration of the study * Subjects receiving FVIII prophylaxis must be willing to discontinue their FVIII prophylactic regimen immediately prior to their second loading dose of Hemlibra (emicizumab) * Subjects receiving bypassing agent prophylaxis must be willing to discontinue their prophylactic regimen at least 24 hours prior to their first loading dose of Hemlibra (emicizumab) * Subjects receiving FVIII ITI therapy must be willing to discontinue ITI immediately prior to their first loading dose of Hemlibra (emicizumab) * Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures, including the health-related questionnaires, activity tracking, and bleed diaries, using systems provided during the study * Adequate hepatic function, defined as total bilirubin ≤1.5 × age-adapted upper limit of normal (ULN) (excluding Gilbert's syndrome) and both AST and ALT ≤3 × age-adapted ULN at the time of screening, and no clinical signs or known laboratory/radiographic evidence consistent with cirrhosis * Subjects must be willing to be vaccinated against HAV and HBV if not previously vaccinated, exposed or immune to HAV or HBV\* * Adequate hematologic function, defined as a platelet count ≥100,000/μL and a PT≤1.5 times the ULN at the time of screening * Adequate renal function, defined as serum creatinine ≤2.5 × age-adapted ULN and creatinine clearance ≥30 mL/min by Cockcroft-Gault formula * For women with hemophilia of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use highly effective contraceptive methods that result in a failure rate of \<1% per year during the treatment period and for at least 5 elimination half-lives (24 weeks) after the last dose of study drug
Exclusion criteria
* Inherited or acquired bleeding disorder other than congenital hemophilia A * Lack of a documented diagnosis of hemophilic pseudotumor * Patients who are at high risk for TMA (eg, have a previous medical or family history of TMA), in the Study Investigator's judgment * History of illicit drug or alcohol abuse within 48 weeks prior to screening, in the Study Investigator's judgment * Previous (within the last 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease * Other conditions (eg, certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis * History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the Emicizumab injection * Planned surgery (excluding minor procedures such as tooth extraction or incision and drainage) during the study * Known HIV infection with CD4 counts \<200 cells/μL. HIV infection with CD4 counts ≥200 cells/μL permitted * Use of systemic immunomodulators (eg, interferon) at enrollment or planned use during the study, with the exception of anti-retroviral therapy * Concomitant disease, condition, significant abnormality on screening evaluations or laboratory tests, or treatment that could interfere with the conduct of the study, or that would, in the opinion of the Study Investigator, pose an additional unacceptable risk in administering study drug to the patient * Receipt of any of the following: * Hemlibra (emicizumab) in a prior investigational study * An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration * A non-hemophilia-related investigational drug within last 30 days or 5 half-lives, whichever is shorter * Any other investigational drug currently being administered or planned to be administered * Inability to comply with the study protocol in the opinion of the Study Investigator * Pregnancy or lactation or intention to become pregnant during the study * Women with a positive serum pregnancy test result within 10 days prior to initiation of study drug
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Hemoglobin | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | Maintenance or increase of hemoglobin (g/dl) from participants' baseline level based on serial blood tests. |
| Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Participants' Need for Blood Transfusions or Lack of | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | Whether or not the patient requires blood transfusions (units of RBCs) due to blood loss secondary to lack of hemostatic efficacy during the duration of study treatment duration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Quality of Life Based on Haem-A-QOL | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | The subjective change in quality of life and activity with Hemlibra (emicizumab) prophylaxis will be evaluated during the study. QoL and activity will be assessed using Haem-A-QoL and EQ-5D-5L. Changes in these measures will be determined by changes from the baseline scores compared to follow-up scores. |
| Patient Quality of Life Based on EQ-5D-5L | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | The subjective change in quality of life and activity with Hemlibra (emicizumab) prophylaxis will be evaluated during the study. QoL and activity will be assessed using Haem-A-QoL and EQ-5D-5L. Changes in these measures will be determined by changes from the baseline scores compared to follow-up scores. |
| Adverse Events | Every 3 months, for the 2 years and 10 months of the patient's study participation duration. | Number of adverse events while on HemLibra (emicizumab) prophylaxis. |
| Serious Adverse Events | Every 3 months, for the 2 years and 10 months of the patient's study participation duration. | Number of SAEs while on HemLibra (emicizumab) prophylaxis |
| Number of Participants With Adverse Events | Every 3 months, for the 2 years and 10 months of the patient's study participation duration. | Number of participants with adverse events while on HemLibra (emicizumab) prophylaxis |
| Breakthrough Bleeds | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | Number of breakthrough bleeding events that require hemostatic therapy in addition to Hemlibra prophylaxis |
| ADA and Activated Partial Thromboplastin Time (APTT) | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | If the patient develops an ADA: the ADA's effect on the patient's APTT |
| ADA and Factor VIII (FVIII) | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | If the patient develops an ADA: the ADA's effecton the patient's FVIII assay |
| Planned or Unplanned Surgery | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | If the patient requires surgery: Whether the procedure(s) was/were planned versus unplanned |
| Hemostatic Agents in Surgery | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | If the patient requires surgery: Whether hemostatic agents in addition to Hemlibra were required to achieve or maintain hemostasis |
| Blood Loss in Surgery | Every 6 months, for the 2 years and 10 months of the patient's study participation duration. | If the patient requires surgery: Whether blood loss exceeded the estimated/predicted blood loss relative to a patient without hemophilia |
| Anti-Drug Antibodies (ADA) | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | Development of emicizumab anti-drug antibodies using the ADA assay |
| Pseudotumor Status | Every 12 months, for the 2 years and 10 months of the patient's study participation duration. | Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization or regression per change in size (measured in cm) of the pseudotumor |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Baseline Characteristics Patients with factor VIII deficiency and a hemophilic pseudotumor. | 1 |
| Total | 1 |
Baseline characteristics
| Characteristic | Baseline Characteristics |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants |
| Age, Continuous | 31 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 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 |
| Region of Enrollment United States | 1 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 1 |
| other Total, other adverse events | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 |
Outcome results
Primary
Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Hemoglobin
Maintenance or increase of hemoglobin (g/dl) from participants' baseline level based on serial blood tests.
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Single Arm | Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Hemoglobin | 9.5 gm/dL |
Primary
Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Participants' Need for Blood Transfusions or Lack of
Whether or not the patient requires blood transfusions (units of RBCs) due to blood loss secondary to lack of hemostatic efficacy during the duration of study treatment duration.
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Single Arm | Hemostatic Efficacy of Prophylactic Weekly Injections of Hemlibra (Emicizumab) Based on Participants' Need for Blood Transfusions or Lack of | 0 Participants |
Secondary
ADA and Activated Partial Thromboplastin Time (APTT)
If the patient develops an ADA: the ADA's effect on the patient's APTT
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient did not develop ADA (anti-drug antibody) during study participation.
Secondary
ADA and Factor VIII (FVIII)
If the patient develops an ADA: the ADA's effecton the patient's FVIII assay
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient did not develop ADA (anti-drug antibody) during study participation.
Secondary
Adverse Events
Number of adverse events while on HemLibra (emicizumab) prophylaxis.
Time frame: Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
Population: AEs were collected during participant's study participation until study treatment / participation withdrawal.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm | Adverse Events | 3 adverse events |
Secondary
Anti-Drug Antibodies (ADA)
Development of emicizumab anti-drug antibodies using the ADA assay
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm | Anti-Drug Antibodies (ADA) | 0 participants |
Secondary
Blood Loss in Surgery
If the patient requires surgery: Whether blood loss exceeded the estimated/predicted blood loss relative to a patient without hemophilia
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient did not have surgery during study participation.
Secondary
Breakthrough Bleeds
Number of breakthrough bleeding events that require hemostatic therapy in addition to Hemlibra prophylaxis
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm | Breakthrough Bleeds | 14 breakthrough bleeding events |
Secondary
Hemostatic Agents in Surgery
If the patient requires surgery: Whether hemostatic agents in addition to Hemlibra were required to achieve or maintain hemostasis
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient did not require surgery during study participation
Secondary
Number of Participants With Adverse Events
Number of participants with adverse events while on HemLibra (emicizumab) prophylaxis
Time frame: Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm | Number of Participants With Adverse Events | 1 participants |
Secondary
Patient Quality of Life Based on EQ-5D-5L
The subjective change in quality of life and activity with Hemlibra (emicizumab) prophylaxis will be evaluated during the study. QoL and activity will be assessed using Haem-A-QoL and EQ-5D-5L. Changes in these measures will be determined by changes from the baseline scores compared to follow-up scores.
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient was unable to return for repeat or final QoL assessments after baseline assessment, due to the COVID19 global pandemic. Only baseline measurements were collected and no follow-up measurements, therefore any change in the QoL status could not be evaluated/determined.
Secondary
Patient Quality of Life Based on Haem-A-QOL
The subjective change in quality of life and activity with Hemlibra (emicizumab) prophylaxis will be evaluated during the study. QoL and activity will be assessed using Haem-A-QoL and EQ-5D-5L. Changes in these measures will be determined by changes from the baseline scores compared to follow-up scores.
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient was unable to return for repeat or final QoL assessments after baseline assessment, due to the COVID19 global pandemic. Only baseline measurements were collected and no follow-up measurements, therefore any change in the QoL status could not be evaluated/determined.
Secondary
Planned or Unplanned Surgery
If the patient requires surgery: Whether the procedure(s) was/were planned versus unplanned
Time frame: Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient did not require surgery during study treatment.
Secondary
Pseudotumor Status
Radiologic evaluation (CT and/or MRI) to evaluate control of progression, stabilization or regression per change in size (measured in cm) of the pseudotumor
Time frame: Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Population: Patient was unable to return for repeat or final assessments of pseudotumor size by radiology scan after baseline assessment due to global COVID19 pandemic. Only baseline measurements were collected and no follow-up measurements, therefore any change in the pseudotumor status could not be evaluated/determined.
Secondary
Serious Adverse Events
Number of SAEs while on HemLibra (emicizumab) prophylaxis
Time frame: Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single Arm | Serious Adverse Events | 0 serious adverse events |