HemLibra Prophylaxis in Patients With Hemophilic Pseudotumor

Prospective, Single-arm, Open-label Use of Hemlibra (Emicizumab) to Treat Hemophilic Pseudotumor

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.

Study Overview

• Status: Terminated
• Conditions: Haemophilic Pseudotumour
• Intervention / Treatment: Drug: Emicizumab

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?

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • Indiana Hemophila @Thrombosis Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: HemLibra

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
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.	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Breakthrough Bleeds	Number of breakthrough bleeding events that require hemostatic therapy in addition to Hemlibra prophylaxis	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
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	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
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.	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
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.	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Adverse Events	Number of adverse events while on HemLibra (emicizumab) prophylaxis.	Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
Serious Adverse Events	Number of SAEs while on HemLibra (emicizumab) prophylaxis	Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
Number of Participants With Adverse Events	Number of participants with adverse events while on HemLibra (emicizumab) prophylaxis	Every 3 months, for the 2 years and 10 months of the patient's study participation duration.
Anti-Drug Antibodies (ADA)	Development of emicizumab anti-drug antibodies using the ADA assay	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
ADA and Activated Partial Thromboplastin Time (APTT)	If the patient develops an ADA: the ADA's effect on the patient's APTT	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
ADA and Factor VIII (FVIII)	If the patient develops an ADA: the ADA's effecton the patient's FVIII assay	Every 12 months, for the 2 years and 10 months of the patient's study participation duration.
Planned or Unplanned Surgery	If the patient requires surgery: Whether the procedure(s) was/were planned versus unplanned	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
Hemostatic Agents in Surgery	If the patient requires surgery: Whether hemostatic agents in addition to Hemlibra were required to achieve or maintain hemostasis	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.
Blood Loss in Surgery	If the patient requires surgery: Whether blood loss exceeded the estimated/predicted blood loss relative to a patient without hemophilia	Every 6 months, for the 2 years and 10 months of the patient's study participation duration.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A; Subcommittee on Factor VIII, Factor IX and Rare Coagulation Disorders of the Scientific and Standardization Committee of the International Society on Thrombosis and Hemostasis. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 2014 Nov;12(11):1935-9. doi: 10.1111/jth.12672. Epub 2014 Sep 3. No abstract available.
• Franchini M, Mannucci PM. Hemophilia A in the third millennium. Blood Rev. 2013 Jul;27(4):179-84. doi: 10.1016/j.blre.2013.06.002. Epub 2013 Jun 28.
• Gringeri A, Leissinger C, Cortesi PA, Jo H, Fusco F, Riva S, Antmen B, Berntorp E, Biasoli C, Carpenter S, Kavakli K, Morfini M, Negrier C, Rocino A, Schramm W, Windyga J, Zulfikar B, Mantovani LG. Health-related quality of life in patients with haemophilia and inhibitors on prophylaxis with anti-inhibitor complex concentrate: results from the Pro-FEIBA study. Haemophilia. 2013 Sep;19(5):736-43. doi: 10.1111/hae.12178. Epub 2013 Jun 4.
• Ahlberg AK. On the natural history of hemophilic pseudotumor. J Bone Joint Surg Am. 1975 Dec;57(8):1133-6.
• Liu SS, White WL, Johnson PC, Gauntt C. Hemophilic pseudotumor of the spinal canal. Case report. J Neurosurg. 1988 Oct;69(4):624-7. doi: 10.3171/jns.1988.69.4.0624.
• Magallon M, Monteagudo J, Altisent C, Ibanez A, Rodriguez-Perez A, Riba J, Tusell J, Martin-Villar J. Hemophilic pseudotumor: multicenter experience over a 25-year period. Am J Hematol. 1994 Feb;45(2):103-8. doi: 10.1002/ajh.2830450202.
• Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llinas A, Ludlam CA, Mahlangu JN, Mulder K, Poon MC, Street A; Treatment Guidelines Working Group on Behalf of The World Federation Of Hemophilia. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47. doi: 10.1111/j.1365-2516.2012.02909.x. Epub 2012 Jul 6.
• van Ommeren JW, Mooren DW, Veth RP, Novakova IR, van de Kaa CA. Pseudotumor occurring in hemophilia. Arch Orthop Trauma Surg. 2000;120(7-8):476-8. doi: 10.1007/s004029900087.

Helpful Links

• Hemophilia Data & Statistics
• What is Hemophilia?
• WFH Guidelines for the management of hemophilia
• WFH report on the annual global survey 2011
• WFH report on the annual global survey 2013
• WFH report on the annual global survey 2015

Study record dates

Study Major Dates

• Study Start (Actual): May 15, 2019
• Primary Completion (Actual): March 16, 2022
• Study Completion (Actual): March 16, 2022

Study Registration Dates

• First Submitted: March 29, 2019
• First Submitted That Met QC Criteria: April 16, 2019
• First Posted (Actual): April 19, 2019

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Other Study ID Numbers: RO-IIS-2018-10581

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.
• IPD Sharing 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.
• IPD Sharing 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.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; CSR

Drug and device information, study documents

• 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