Study Results
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Basic Information
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RECRUITING
PHASE4
95 participants
INTERVENTIONAL
2022-09-08
2026-08-31
Brief Summary
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A Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Given Every 4 Weeks in Participants With Hemophilia A
NCT03020160
A Study to Evaluate the Safety, Efficacy, Pharmacokinetics and Pharmacodynamics of Emicizumab in Participants With Mild or Moderate Hemophilia A Without FVIII Inhibitors
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Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures
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A Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors
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Emicizumab in Acquired Hemophilia A
NCT04188639
Detailed Description
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Prophylaxis with FVIII concentrates has effectively reduced treated bleeds from an annual average of 20-30 to 1-4. However, in approximately 30% of PwHA anti-FVIII antibodies (known as inhibitors) develop that interfere with FVIII replacement therapy. PwHA who develop inhibitors require alternative suboptimal therapy with (costly) bypassing agents (BPA).
The first approved non-factor therapy is the bispecific, FVIII-mimicking antibody, emicizumab (Hemlibra®), which came available in the Netherlands in July 2018. Emicizumab is a humanized, bispecific antibody connecting factor IX and factor X enabling the activation of FX and subsequent thrombin generation. Emicizumab has shown to be highly effective prophylaxis in PwHA by achieving a complete eradication of treated bleeds in around 80% of PwHA (n = 374) during the second 24-week interval of treatment. Furter advantages of emicizumab are the subcutaneous administration and less frequent dosing intervals every 1, 2 or 4 weeks due to a long half-life (t ½: 28 days). Despite many PwHA are candidate for prophylaxis with emicizumab, cost limit widespread access.
Currently, emicizumab is approved by F. Hoffmann-La Roche® with a loading dose of 3 mg/kg/week for four weeks and a maintenance dose of 1.5 mg/kg/week, 3 mg/kg/2 weeks or 6 mg/kg/4 weeks. These dose regimens were based on a pharmacometric approach instead of a dose finding study, and targeted a trough concentration (Ctrough) of 45 µg/ml by using pharmacokinetic (PK)simulations. Meanwhile long-term bleed data from the phase III and IV studies by the pharmaceutical company were included in pharmacokinetic (PK) and pharmacodynamic (PD) modelling studies, and the effective Ctrough was suggested at 30 µg/ml.
Although this Ctrough of 30 µg/ml is substantially lower than the previous Ctrough (45 µg/ml), the dose regimens were not adjusted. Conventional dosing leads to mean concentrations of 55 µg/ml with two thirds of the observations between 40 and 70 µg/ml (i.e., SD of ±15 µg/ml). Emicizumab has been approved based on fixed body-weight-based dosing and therefore the concentration target might have been kept higher to avoid lower effectivity due to inter-patient variability. However, reduced dosing of emicizumab, either by extending the dosing interval or lowering the dose, without sacrificing its efficacy has been reported in small case series.
Therefore, the investigators hypothesized that lower dosing of emicizumab targeted at Ctrough 30 μg/mL, is equally as effective and less costly in preventing bleeds as conventional dosing of emicizumab, and designed the DosEmi study to investigate the hypothesis in a large prospective cohort of adult and paediatric PwHA.
Conditions
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Study Design
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NON_RANDOMIZED
CROSSOVER
* PK-Guided dosing - Non-intervention group (12M): Subjects with emicizumab concentration of 25-39 μg/mL will continue on their current dose regimen and will be followed according to the same assessment schedule as the Intervention Group. Only subjects with emicizumab plasma concentration \< 25 μg/mL will be adjusted in dosing regimen according to local protocol. These subjects will be followed for selective safety data only.
TREATMENT
NONE
Study Groups
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Conventional dosing - open label
Patients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing.
Emicizumab - PK-guided dose reduction
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Emicizumab - Dosis continuation group
Continue on their current dose regimen
Emicizumab - Dose adjustment group
Adjusted in dosing regimen according to local protocol
PK-guided dosing - open label
Patients with emicizumab concentration of ≥ 40 μg/mL will receive individualized PK-guided dose reduction of emicizumab targeted at a Ctrough of 30μg/mL. Patients will be followed for 12 months on reduced dosing.
Emicizumab - PK-guided dose reduction
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
No intervention continuation - open label
Patients with emicizumab concentration of 25-39 μg/mL will continue on their current dose regimen. Patients will be followed for 12 months on current dosing.
Emicizumab - Dosis continuation group
Continue on their current dose regimen
No intervention adjusted - open label
Patients with emicizumab plasma concentration \< 25 μg/mL will be adjusted in dosing regimen according to local protocol. Patients will be followed for selective safety data only.
Emicizumab - Dose adjustment group
Adjusted in dosing regimen according to local protocol
Interventions
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Emicizumab - PK-guided dose reduction
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Emicizumab - Dosis continuation group
Continue on their current dose regimen
Emicizumab - Dose adjustment group
Adjusted in dosing regimen according to local protocol
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Aged \> 1 year at inclusion (inclusion of children 1-16 years after favourable interim-analysis see protocol)
* Receiving conventional dosing of emicizumab (6 mg/kg/4 weeks with varying intervals) for a duration of at least 12 months prior to inclusion;
* Having good bleeding control, defined as:
i No spontaneous joint/muscle bleeds in the previous 6 months AND ii A maximum of two treated (traumatic) bleeds in the previous 6 months.
* Willing and able to provide written informed consent, either by the subject or its parents/legal guardian
* Willing to provide bleeding assessment information
* Willing to adhere to the medication regimen
Exclusion Criteria
1 Year
MALE
No
Sponsors
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Erasmus Medical Center
OTHER
Amsterdam University Medical Center
OTHER
Leiden University Medical Center
OTHER
Radboud University Medical Center
OTHER
Maastricht University Medical Center
OTHER
University Medical Center Groningen
OTHER
HagaZiekenhuis
OTHER
Dutch Society of Haemophilia Patients
UNKNOWN
Kathelijn Fischer
OTHER
Responsible Party
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Kathelijn Fischer
Principal Investigator
Principal Investigators
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Study Officials Fischer, Dr, MD
Role: PRINCIPAL_INVESTIGATOR
UMC Utrecht
Locations
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Radboud University Medical Center
Nijmegen, Gelderland, Netherlands
Maastricht University Medical Center
Maastricht, Limburg, Netherlands
Amsterdam University Medical Center
Amsterdam, North Holland, Netherlands
Leids Universitair Medisch Centrum
Leiden, South Holland, Netherlands
Erasmus University Medical Center
Rotterdam, South Holland, Netherlands
HagaZiekenhuis
The Hague, South Holland, Netherlands
University Medical Center Groningen
Groningen, , Netherlands
University Medical Center Utrecht
Utrecht, , Netherlands
Countries
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Central Contacts
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Facility Contacts
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References
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Donners A, van der Zwet K, Egberts ACG, Fijnvandraat K, Mathot R, Kruis I, Cnossen MH, Schutgens R, Urbanus RT, Fischer K. DosEmi study protocol: a phase IV, multicentre, open-label, crossover study to evaluate non-inferiority of pharmacokinetic-guided reduced dosing compared with conventional dosing of emicizumab in people with haemophilia A. BMJ Open. 2023 Jun 26;13(6):e072363. doi: 10.1136/bmjopen-2023-072363.
Berntorp E, Fischer K, Hart DP, Mancuso ME, Stephensen D, Shapiro AD, Blanchette V. Haemophilia. Nat Rev Dis Primers. 2021 Jun 24;7(1):45. doi: 10.1038/s41572-021-00278-x.
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.
Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, Carcao M, Mahlangu J, Ragni MV, Windyga J, Llinas A, Goddard NJ, Mohan R, Poonnoose PM, Feldman BM, Lewis SZ, van den Berg HM, Pierce GF; WFH Guidelines for the Management of Hemophilia panelists and co-authors. WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 Aug;26 Suppl 6:1-158. doi: 10.1111/hae.14046. Epub 2020 Aug 3. No abstract available.
Callaghan MU, Negrier C, Paz-Priel I, Chang T, Chebon S, Lehle M, Mahlangu J, Young G, Kruse-Jarres R, Mancuso ME, Niggli M, Howard M, Bienz NS, Shima M, Jimenez-Yuste V, Schmitt C, Asikanius E, Levy GG, Pipe SW, Oldenburg J. Long-term outcomes with emicizumab prophylaxis for hemophilia A with or without FVIII inhibitors from the HAVEN 1-4 studies. Blood. 2021 Apr 22;137(16):2231-2242. doi: 10.1182/blood.2020009217.
Yoneyama K, Schmitt C, Kotani N, Levy GG, Kasai R, Iida S, Shima M, Kawanishi T. A Pharmacometric Approach to Substitute for a Conventional Dose-Finding Study in Rare Diseases: Example of Phase III Dose Selection for Emicizumab in Hemophilia A. Clin Pharmacokinet. 2018 Sep;57(9):1123-1134. doi: 10.1007/s40262-017-0616-3.
Retout S, Schmitt C, Petry C, Mercier F, Frey N. Population Pharmacokinetic Analysis and Exploratory Exposure-Bleeding Rate Relationship of Emicizumab in Adult and Pediatric Persons with Hemophilia A. Clin Pharmacokinet. 2020 Dec;59(12):1611-1625. doi: 10.1007/s40262-020-00904-z.
Jonsson F, Schmitt C, Petry C, Mercier F, Frey N, Retout S. Exposure-Bleeding Count Modeling of Emicizumab for the Prophylaxis of Bleeding in Persons with Hemophilia A with/Without Inhibitors Against Factor VIII. Clin Pharmacokinet. 2021 Jul;60(7):931-941. doi: 10.1007/s40262-021-01006-0. Epub 2021 Mar 12.
Donners AAMT, Rademaker CMA, Bevers LAH, Huitema ADR, Schutgens REG, Egberts TCG, Fischer K. Pharmacokinetics and Associated Efficacy of Emicizumab in Humans: A Systematic Review. Clin Pharmacokinet. 2021 Nov;60(11):1395-1406. doi: 10.1007/s40262-021-01042-w. Epub 2021 Aug 13.
Lehtinen AE, Lassila R. Do we need all that emicizumab? Haemophilia. 2022 Mar;28(2):e53-e55. doi: 10.1111/hae.14483. Epub 2021 Dec 30. No abstract available.
Chuansumrit A, Sirachainan N, Jaovisidha S, Jiravichitchai T, Kadegasem P, Kempka K, Panuwannakorn M, Rotchanapanya W, Nuntiyakul T. Effectiveness of monthly low dose emicizumab prophylaxis without 4-week loading doses among patients with haemophilia A with and without inhibitors: A case series report. Haemophilia. 2023 Jan;29(1):382-385. doi: 10.1111/hae.14707. Epub 2022 Nov 29. No abstract available.
Bansal S, Donners AAMT, Fischer K, Kshirsagar S, Rangarajan S, Phadke V, Mhatre S, Sontate B, Silva M, Ansari S, Shetty S. Low dose emicizumab prophylaxis in haemophilia a patients: A pilot study from India. Haemophilia. 2023 May;29(3):931-934. doi: 10.1111/hae.14785. Epub 2023 Apr 8. No abstract available.
Study Documents
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Other Identifiers
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22-571
Identifier Type: -
Identifier Source: org_study_id
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