Clinical trial NCT06320626: Pharmacokinetic-guided Dosing of Emicizumab
Official title: Pharmacokinetic-guided Dosing of Emicizumab in Congenital Haemophilia A Patients - The DosEmi Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Hemophilia A With Inhibitor
Hemophilia A Without Inhibitor
Hemophilia A, Severe
Adolescent
Child
Adult
Keywords: Emicizumab
Hemophilia A
Monoclonal antibodies
PK-guided dosing
Hemorrhage
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
Collaborators: name: Erasmus Medical Center
name: Amsterdam University Medical Center
name: Leiden University Medical Center
name: Radboud University Medical Center
name: Maastricht University Medical Center
name: University Medical Center Groningen
name: HagaZiekenhuis
name: Dutch Society of Haemophilia Patients
First posted: 2024-03-20
Enrollment: 95
Sex: MALE
Minimum age (years): 1
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: * PK-guided dosing - Intervention group (12M): Subjects with emicizumab concentration of ≥ 40 μg/mL will receive individualized PK-guided dose reduction of emicizumab targeted at a Ctrough of 30μg/mL. The validated population PK model is based on published population PK and PK/PD modelling studies. (9,10,15)
* 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.
Primary purpose: TREATMENT

Brief summary: The goal of this multicentre, prospective, open-label, cross-over clinical study is to determine whether individualized PK-guided dosing of emicizumab is non-inferior to conventional dosing of emicizumab in the prevention of bleeding in congenital haemophilia A patients.

Detailed description: Haemophilia A is an X-linked hereditary bleeding disorder resulting from a deficiency or dysfunction of endogenous coagulation factor VIII (FVIII). Persons with haemophilia A (PwHA) suffer from spontaneous or provoked bleeding, predominantly into major joints, which eventually lead to painful and chronic disabling arthropathy. The primary goal in clinical management of haemophilia A is prevention of bleeding by self-administration of FVIII concentrates via intravenous injections.

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.

Eligibility criteria: Inclusion Criteria:

* Confirmed diagnosis of congenital haemophilia A, with a baseline endogenous FVIII of \<6 IU/ml
* 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:

* Acquired haemophilia A

Primary outcomes:
measure: Proportion of patients without treated bleeds
timeFrame: 12 months
Secondary outcomes:
measure: Proportion of patients without treated bleeds
timeFrame: 24 months
measure: Proportion of patients without spontaneous joint- or muscle bleeds
timeFrame: 24 months
measure: Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds
timeFrame: 24 months
measure: To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab
timeFrame: 24 months
measure: To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.
timeFrame: 24 months
measure: To assess the performance of the population PK model
timeFrame: 12 months
measure: To investigate whether direct joint health remains stable measured by physical examination when switching to lower-dosed emicizumab compared to conventional treatment
timeFrame: 12 months
measure: To investigate whether direct joint health remains stable measured by ultrasound when switching to lower-dosed emicizumab compared to conventional treatment
timeFrame: 12 months
measure: To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
timeFrame: 12 months
measure: To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
timeFrame: 12 months
measure: To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
timeFrame: 12 months
measure: To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
timeFrame: 12 months
measure: To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
timeFrame: 12 months
measure: To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy.
timeFrame: 12 months
measure: To assess and monitor pain during emicizumab administration
timeFrame: 12 months
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboud University Medical Center
state: Gelderland
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Center
state: Noord-Holland
city: Den Haag
country: Netherlands
facility: HagaZiekenhuis
state: Zuid-Holland
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid-Holland
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
state: Zuid-Holland
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
city: Utrecht
country: Netherlands
facility: University Medical Center Utrecht
Study officials:
affiliation: UMC Utrecht
name: Study Officials Fischer, Dr, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
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citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.