Global COVID-19 pandemic prevented further study visits or enrollment.

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.

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?

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

We will share resources and data from this project through collaborative publications in the scientific literature as well as through national, regional and international conference presentations. We will also share our methods and findings in a prompt manner with regional, national and international stakeholders to ensure that findings will be readily available to other researchers and clinicians with clinical or scientific interest in the subject area. Individual participant data that underlie the results reports in publications, reports or presentations (including text, tables, figures and appendices) will be shared after de-identification.

IPD and additional information on study methods will be made available starting 9 months after publication or conclusion of the study and ending 36 months following publication or study conclusion.

IPD and study information will be shared with investigators whose proposed use of the data has been approved by an independent review committee ("learned intermediary"), whose proposals are methodologically sound, and for purposes that are consistent with the aims of the underlying research. Proposals will be reviewed by the Principle Investigator, Dr. Amy Shapiro, and may be submitted to ashapiro@ihtc.org. Requestors will be required to sign a data access and use agreement.

Patients with Factor VIII deficiency and hemophilia pseudotumor.

Every 3 months, for the 2 years and 10 months of the patient's study participation duration.

Standard definitions