Hemlibra in Mild Hemophilia A

NCT04567511 | Recruiting Phase 4 DMC FDA Drug

• 1 other identifier: RO-IIS-2019-20049
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief Summary

This is a single arm, phase 4, prospective, open-label, United States single-center study to determine the hemostatic characteristics of Hemlibra (emicizumab) as measured by coagulation laboratory parameters in the mild hemophilia A male patient population with endogenous altered FVIII (baseline FVIII activity of \>5% to 30%). The safety and hemostatic efficacy of Hemlibra (emicizumab) in this patient population will be investigated. Secondary outcomes will assess changes in joint health and quality of life in treated patients.

Conditions

Factor VIII Deficiency, Congenital

Keywords

hemophilia A; mild hemophilia A; Factor VIII deficiency

Outcome Measures

Primary Outcomes (1)

• Interaction of Hemlibra (emicizumab) binding with endogenous altered FVIII protein in an individual with mild hemophilia A and the combined effect on thrombin generation and hemostatic characteristics

  Change in FVIII human chromogenic activity, FVIII bovine chromogenic activity, and Thrombin Generation Assay relatively to one another

  Before treatment, month 4, month 7, and month 13

Secondary Outcomes (8)

• Breakthrough bleeds

  Through study completion, up to 35 months

• Factor VIII alteration and coagulation

  Before treatment, month 4, month 7, and month 13

• Change from baseline joint disease annually

  Through study completion annually, up to 35 months

• AE, SAE, and ADA

  Through study completion annually, up to 35 months

• ADA development

  ADA assay at month 4, month 7, month 13, and end of study participation

Study Arms (1)

Single Arm

EXPERIMENTAL

Patients with mild hemophilia A (without inhibitors) will be treated with prophylactic emicizumab. The clinical hemostatic efficacy and safety will be assessed. Secondary outcomes will assess changes in quality of life and joint health in treated patients.

Drug: Emicizumab

Interventions

Emicizumab DRUG

bispecific monoclonal antibody binding to activated Factor IX and Factor X

Also known as: Hemlibra

Single Arm

Eligibility Criteria

• Age: 5 Years - 45 Years
• Gender Eligibility Details: only males will be enrolled in the study.
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Signed informed consent form from the subject, parent or guardian
• Male sex
• Diagnosis of mild congenital hemophilia A (baseline FVIII level of \>5% to 30%) without a current FVIII inhibitor or a history of FVIII inhibitor
• Any number of FVIII exposure days, including PUPs
• BMI \<30
• Age ≥5 years to ≤45 years
• Medical documentation of bleeding events, outcomes and hemostatic product usage for 12 months prior to study enrollment
• 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
• Willingness to undergo a Stimate/DDAVP challenge (only if the subject reports no adverse event associated with prior Stimate \[DDAVP/desmopressin acetate\] use); Stimate/DDAVP challenge will not be performed if the patient has a documented history of lack of response as defined by an increase of FVIII \< 2 times baseline level
• 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
• 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

You may not qualify if:

• Inherited or acquired bleeding disorder other than mild congenital hemophilia A (baseline FVIII level of \>5% to 30%)
• Any bleeding disorder other than or in addition to mild hemophilia A
• Current or prior inhibitor to FVIII (any titer)
• Female sex
• History of CVD, risk of CVD by the ASCVD risk estimator (defined as a subject having \>20% risk of a cardiovascular event within the next 10 years if the subject is ≥20 years of age) and/or a history of ischemic heart disease \[ICD codes 120-125\]
• 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 by report or 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 Hemlibra (emicizumab) injection
• 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

Sponsors & Collaborators

• Indiana Hemophilia &Thrombosis Center, Inc.: lead
• Genentech, Inc.: collaborator

Study Sites (1)

Indiana Hemophila @Thrombosis Center

Indianapolis, Indiana, 46260, United States

RECRUITING

Related Publications (24)

• Batorova A, Holme P, Gringeri A, Richards M, Hermans C, Altisent C, Lopez-Fernandez M, Fijnvandraat K; European Haemophilia Treatment Standardisation Board. Continuous infusion in haemophilia: current practice in Europe. Haemophilia. 2012 Sep;18(5):753-9. doi: 10.1111/j.1365-2516.2012.02810.x. Epub 2012 Apr 25.

  PMID: 22530687 RESULT

• 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.

  PMID: 25059285 RESULT

• Centers for Disease Control and Prevention (2014). Hemophilia Data & Statistics Retrieved April 22, 2014, from http://www.cdc.gov/ncbddd/hemophilia/data.html

  RESULT

• Franchini M, Favaloro EJ, Lippi G. Mild hemophilia A. J Thromb Haemost. 2010 Mar;8(3):421-32. doi: 10.1111/j.1538-7836.2009.03717.x. Epub 2009 Dec 7.

  PMID: 19995408 RESULT

• 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.

  PMID: 23815950 RESULT

• Franchini M, Mannucci PM. Inhibitor eradication with rituximab in haemophilia: where do we stand? Br J Haematol. 2014 Jun;165(5):600-8. doi: 10.1111/bjh.12829. Epub 2014 Mar 15.

  PMID: 24628543 RESULT

• 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.

  PMID: 23731246 RESULT

• Hay CR. Factor VIII inhibitors in mild and moderate-severity haemophilia A. Haemophilia. 1998 Jul;4(4):558-63. doi: 10.1046/j.1365-2516.1998.440558.x.

  PMID: 9873794 RESULT

• Kempton CL, Allen G, Hord J, Kruse-Jarres R, Pruthi RK, Walsh C, Young G, Soucie JM. Eradication of factor VIII inhibitors in patients with mild and moderate hemophilia A. Am J Hematol. 2012 Sep;87(9):933-6. doi: 10.1002/ajh.23269. Epub 2012 Jun 26.

  PMID: 22733686 RESULT

• Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso ME, Schmitt C, Jimenez-Yuste V, Kempton C, Dhalluin C, Callaghan MU, Bujan W, Shima M, Adamkewicz JI, Asikanius E, Levy GG, Kruse-Jarres R. Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med. 2018 Aug 30;379(9):811-822. doi: 10.1056/NEJMoa1803550.

  PMID: 30157389 RESULT

• Makris M, Oldenburg J, Mauser-Bunschoten EP, Peerlinck K, Castaman G, Fijnvandraat K; subcommittee on Factor VIII, Factor IX and Rare Bleeding Disorders. The definition, diagnosis and management of mild hemophilia A: communication from the SSC of the ISTH. J Thromb Haemost. 2018 Dec;16(12):2530-2533. doi: 10.1111/jth.14315. Epub 2018 Nov 15. No abstract available.

  PMID: 30430726 RESULT

• National Institutes of Health (2014). What Is Hemophilia? Retrieved April 22, 2014, from https://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/

  RESULT

• Oldenburg J, Mahlangu JN, Kim B, Schmitt C, Callaghan MU, Young G, Santagostino E, Kruse-Jarres R, Negrier C, Kessler C, Valente N, Asikanius E, Levy GG, Windyga J, Shima M. Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med. 2017 Aug 31;377(9):809-818. doi: 10.1056/NEJMoa1703068. Epub 2017 Jul 10.

  PMID: 28691557 RESULT

• Pezeshkpoor B, Gazorpak M, Berkemeier AC, Singer H, Pavlova A, Biswas A, Oldenburg J. In silico and in vitro evaluation of the impact of mutations in non-severe haemophilia A patients on assay discrepancies. Ann Hematol. 2019 Aug;98(8):1855-1865. doi: 10.1007/s00277-019-03691-1. Epub 2019 Apr 17.

  PMID: 30997536 RESULT

• Pipe, S. (2018). Emicizumab subcutaneous dosing every 4 weeks is safe and efficacious in the control of bleeding in persons with haemophilia A with and without inhibitors - Results from the phase 3 HAVEN 4 study. World Federation of Hemophila World Congress Glasgow, Scotland.

  RESULT

• Prelog T, Dolnicar MB, Kitanovski L. Low-dose continuous infusion of factor VIII in patients with haemophilia A. Blood Transfus. 2016 Sep;14(5):474-80. doi: 10.2450/2015.0080-15. Epub 2015 Nov 16.

  PMID: 26674820 RESULT

• Sengupta M, Sarkar D, Ganguly K, Sengupta D, Bhaskar S, Ray K. In silico analyses of missense mutations in coagulation factor VIII: identification of severity determinants of haemophilia A. Haemophilia. 2015 Sep;21(5):662-9. doi: 10.1111/hae.12662. Epub 2015 Apr 9.

  PMID: 25854144 RESULT

• Shima, M., K. Nogami, S. Nagami, S. Yoshida, K. Yoneyama, A. Ishiguro, T. Suzuki and M. Taki (2018) Every 2 Weeks or Every 4 Weeks Subcutaneous Injection of Emicizumab in Pediatric Patients with Severe Hemophilia A without Inhibitors: A Multi-Center, Open-Label Study in Japan (HOHOEMI Study). Blood 132:1186-1186.

  RESULT

• World Federation of Hemophilia (2012). Guidelines for the management of hemophilia Retrieved February 16, 2015, from http://www1.wfh.org/publication/files/pdf-1472.pdf

  RESULT

• World Federation of Hemophilia (2012). World Federation of Hemophilia report on the annual global survey 2011 Retrieved December 20, 2016, from http://www1.wfh.org/publication/files/pdf-1488.pdf

  RESULT

• World Federation of Hemophilia (2013). World Federation of Hemophilia report on the annual global survey 2013 Retrieved February 5, 2015, from http://www1.wfh.org/publications/files/pdf-1591.pdf

  RESULT

• World Federation of Hemophilia (2016). World Federation of Hemophilia report on the annual global survey 2015 Retrieved December 20, 2016, from http://www1.wfh.org/publication/files/pdf-1669.pdf.

  RESULT

• World Federation of Hemophilia (2017). World Federation of Hemophilia Annual Global Survey Data Retrieved May 30, 2017, from https://www.wfh.org/en/resources/annual-global-survey

  RESULT

• Young G, Liesner R, Chang T, Sidonio R, Oldenburg J, Jimenez-Yuste V, Mahlangu J, Kruse-Jarres R, Wang M, Uguen M, Doral MY, Wright LY, Schmitt C, Levy GG, Shima M, Mancuso ME. A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood. 2019 Dec 12;134(24):2127-2138. doi: 10.1182/blood.2019001869.

  PMID: 31697801 RESULT

MeSH Terms

Conditions

Hemophilia A

Interventions

emicizumab

Condition Hierarchy (Ancestors)

Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• Amy D Shapiro, MD

  Indiana Hemophilia &Thrombosis Center, Inc.

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Amy D Shapiro, MD

CONTACT

3178710000; ashapiro@ihtc.org

Usha Sirimalle, MS

CONTACT

3178710000; usirimalle@ihtc.org

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Director

Model Details: single arm prospective open-label single-center study

Study Record Dates

• First Submitted: July 29, 2020
• First Posted: September 28, 2020
• Study Start: July 25, 2022
• Primary Completion: July 1, 2025
• Study Completion (Estimated): July 1, 2027
• Last Updated: March 15, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (1)