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HemLibra Prophylaxis in Patients With Hemophilic Pseudotumor

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ClinicalTrials.gov Identifier: NCT03921294
Recruitment Status : Not yet recruiting
First Posted : April 19, 2019
Last Update Posted : April 19, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Amy D Shapiro, MD, Indiana Hemophilia &Thrombosis Center, Inc.

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.

Condition or disease Intervention/treatment Phase
Haemophilic Pseudotumour Drug: Emicizumab Phase 4

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?


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 participants
Intervention Model: Single Group Assignment
Intervention Model Description: single arm prospective open-label single-center study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective, Single-arm, Open-label Use of Hemlibra (Emicizumab) to Treat Hemophilic Pseudotumor
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : May 2023
Estimated Study Completion Date : May 2023

Resource links provided by the National Library of Medicine

Drug Information available for: Emicizumab

Arm Intervention/treatment
Experimental: Single Arm
Patients with hemophilic pseudotumor will be treated with prophylactic emicizumab and assessed for improvement.
Drug: Emicizumab
bispecific monoclonal antibody binding to activated Factor IX and Factor X
Other Name: HemLibra




Primary Outcome Measures :
  1. Hemostatic efficacy of prophylactic weekly injections of Hemlibra (emicizumab) based on hemoglobin [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Serial measurements of hemoglobin (g/dl)

  2. Hemostatic efficacy of prophylactic weekly injections of Hemlibra (emicizumab) based on blood transfusions [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Whether or not the patient requires blood transfusions (units of RBCs)


Secondary Outcome Measures :
  1. Breakthrough bleeds [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Number of breakthrough bleeding events that require hemostatic therapy in addition to Hemlibra prophylaxis

  2. Pseudotumor Status [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Size of the pseudotumor based upon CT scans (size in cm)

  3. Patient Quality of Life based on Haem-A-QOL [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Patient subjective QOL measurement as measured by Haem-A-QOL questionnaire

  4. Patient Quality of Life based on EQ-5D-5L [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Patient subjective QOL measurement as measured by EQ-5D-5L questionnaire

  5. Adverse Events [ Time Frame: Every 3 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Number of adverse events while on HemLibra (emicizumab) prophylaxis

  6. Serious Adverse Events [ Time Frame: Every 3 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Number of SAEs while on HemLibra (emicizumab) prophylaxis

  7. Number of participants with adverse events [ Time Frame: Every 3 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Number of participants with adverse events while on HemLibra (emicizumab) prophylaxis

  8. Anti-Drug Antibodies (ADA) [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    Development of emicizumab anti-drug antibodies using the ADA assay

  9. ADA and Activated Partial Thromboplastin Time (APTT) [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    If the patient develops an ADA: the ADA's effect on the patient's APTT

  10. ADA and Factor VIII (FVIII) [ Time Frame: Every 12 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    If the patient develops an ADA: the ADA's effecton the patient's FVIII assay

  11. Planned or unplanned surgery [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    If the patient requires surgery: Whether the procedure(s) was/were planned versus unplanned

  12. Hemostatic agents in surgery [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    If the patient requires surgery: Whether hemostatic agents in addition to Hemlibra were required to achieve or maintain hemostasis

  13. Blood loss in surgery [ Time Frame: Every 6 months, up to 4 years (Minimum of 2 years, maximum of 4 years) ]
    If the patient requires surgery: Whether blood loss exceeded the estimated/predicted blood loss relative to a patient without hemophilia



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03921294


Contacts
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Contact: Amy D Shapiro, MD 3178710000 ashapiro@ihtc.org
Contact: Kathleen F Betbadal, BSN 3178710011 ext 287 kbetbadal@ihtc.org

Sponsors and Collaborators
Indiana Hemophilia &Thrombosis Center, Inc.
Genentech, Inc.
Investigators
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Principal Investigator: Amy D Shapiro, MD Indiana Hemophilia &Thrombosis Center, Inc.

Additional Information:
Publications of Results:

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Responsible Party: Amy D Shapiro, MD, Medical Director, Indiana Hemophilia &Thrombosis Center, Inc.
ClinicalTrials.gov Identifier: NCT03921294     History of Changes
Other Study ID Numbers: RO-IIS-2018-10581
First Posted: April 19, 2019    Key Record Dates
Last Update Posted: April 19, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Clinical Study Report (CSR)
Time Frame: 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.
Access Criteria: 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.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Antibodies, Bispecific
Immunologic Factors
Physiological Effects of Drugs