Pharmacokinetic-guided Dosing of Emicizumab

Child Clinical Trial

— DosEmi  

Official title:

Pharmacokinetic-guided Dosing of Emicizumab in Congenital Haemophilia A Patients - The DosEmi Study

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06320626
• Other study ID #: 22-571
• Status: Recruiting
• Phase: Phase 4
• Start date: September 8, 2022
• Est. completion date: August 2026

Study information

• Verified date: March 2024
• Source: UMC Utrecht
• Contact: Kathelijn Fischer, Dr, MD.
• Phone: +318 875 584 50
• Email: k.fischer[@]umcutrecht.nl
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 95
• Est. completion date: August 2026
• Est. primary completion date: March 2026
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 1 Year and older

Eligibility

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

Related Conditions & MeSH terms

• Adolescent
• Adult
• Child
• Hemophilia A
• Hemophilia A With Inhibitor
• Hemophilia A Without Inhibitor
• Hemophilia A, Severe

Intervention

Other:
• 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

Locations

Country	Name	City	State
Netherlands	Amsterdam University Medical Center	Amsterdam	Noord-Holland
Netherlands	HagaZiekenhuis	Den Haag	Zuid-Holland
Netherlands	University Medical Center Groningen	Groningen
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid-Holland
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Radboud University Medical Center	Nijmegen	Gelderland
Netherlands	Erasmus University Medical Center	Rotterdam	Zuid-Holland
Netherlands	University Medical Center Utrecht	Utrecht

Sponsors (9)

Lead Sponsor	Collaborator
Kathelijn Fischer	Amsterdam University Medical Center, Dutch Society of Haemophilia Patients, Erasmus Medical Center, HagaZiekenhuis, Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center, University Medical Center Groningen

Country where clinical trial is conducted

Netherlands, 

References & Publications (12)

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. — View 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. — View 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. — View 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. Erratum In: Blood. 2023 Oct 12;142(15):1329. — View 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. — View 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. — View 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. — View 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. — View 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. — View 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. — View Citation

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. Erratum In: Haemophilia. 2021 Jul;27(4):699. — View 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. — View Citation

* Note: There are 12 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of patients without treated bleeds	Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)	12 months
Secondary	Proportion of patients without treated bleeds	Comparison proportion without treated bleeds 12 months before (conventional) and after intervention (PK-guided dosing)	24 months
Secondary	Proportion of patients without spontaneous joint- or muscle bleeds	Comparison proportion without spontaneous joint- or muscle bleeds 6 and 12 months before and after intervention.	24 months
Secondary	Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds	Comparison annualized bleeding rate 6 and 12 months before and after intervention.	24 months
Secondary	To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab	Direct and indirect medical costs: Direct medical costs are predominantly determined by consumption of emicizumab, additional FVIII, and/or bypassing agents, extracted from the hospital's pharmacy records. These data are highly reliable, as this medication is exclusively distributed by haemophilia treatment centers. Indirect medical costs: are number of (emergency) hospital visits, bleeding related hospital admissions and/or unscheduled surgeries, and days lost from work/school (for patients and/or caregivers).	24 months
Secondary	To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.	Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction.	24 months
Secondary	To assess the performance of the population PK model	Predictive performance of the MAP Bayesian procedure used for the dose adaptation procedure, defined as % of patients within ±20% of target level/within the target level of 25-39 µg/mL of emicizumab.	12 months
Secondary	To investigate whether direct joint health remains stable measured by physical examination when switching to lower-dosed emicizumab compared to conventional treatment	Joint status will be measured by physical examination (Haemophilia Joint Health Score; HJHS),	12 months
Secondary	To investigate whether direct joint health remains stable measured by ultrasound when switching to lower-dosed emicizumab compared to conventional treatment	Joint status will be measured by ultrasound (if available, according to the HEAD US score).	12 months
Secondary	To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.	biomarker assessment for inflammation and joint and cartilage turnover in blood. The biomarkers comprising origin of different joint tissues will be selected and adopted based on the literature on osteoarthritis, which is a rapidly changing area of research.	12 months
Secondary	To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.	biomarker assessment for inflammation and joint and cartilage turnover in urine.The biomarkers comprising origin of different joint tissues will be selected and adopted based on the literature on osteoarthritis, which is a rapidly changing area of research.	12 months
Secondary	To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.	Health related quality of life will be assessed with EuroQol Five Dimensions Health Questionnaire (Youth) EQ5D(Y).	12 months
Secondary	To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.	Health related quality of life will be assed with PROMIS instruments (Physical Function/mobility and Pain Interference short forms).	12 months
Secondary	To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.	Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ).	12 months
Secondary	To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy.	To measure coagulation potential, blood samples will be collected to measure thrombin generation (Peak Height and ETP)	12 months
Secondary	To assess and monitor pain during emicizumab administration	Assessment of pain during emicizumab administration by Visual Analogue Scale (scale 0-10)	12 months