Pharmacokinetic-guided Dosing of Emicizumab

NCT06320626 | Recruiting Phase 4 DMC

• 1 other identifier: 22-571
• Study Type: interventional
• Target: 95
• Locations: 1 country
• Sites: 8

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.

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

Outcome Measures

Primary Outcomes (1)

• Proportion of patients without treated bleeds

  Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)

  12 months

Secondary Outcomes (15)

• Proportion of patients without treated bleeds

  24 months

• Proportion of patients without spontaneous joint- or muscle bleeds

  24 months

• Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds

  24 months

• To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab

  24 months

• To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.

  24 months

Study Arms (4)

Conventional dosing - open label

OTHER

Patients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing.

Other: Emicizumab - PK-guided dose reduction; Other: Emicizumab - Dosis continuation group; Other: Emicizumab - Dose adjustment group

PK-guided dosing - open label

OTHER

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.

Other: Emicizumab - PK-guided dose reduction

No intervention continuation - open label

OTHER

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.

Other: Emicizumab - Dosis continuation group

No intervention adjusted - open label

OTHER

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.

Other: Emicizumab - Dose adjustment group

Interventions

Emicizumab - PK-guided dose reduction OTHER

PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.

Also known as: Hemlibra

Conventional dosing - open label; PK-guided dosing - open label

Emicizumab - Dosis continuation group OTHER

Continue on their current dose regimen

Also known as: Hemlibra

Conventional dosing - open label; No intervention continuation - open label

Emicizumab - Dose adjustment group OTHER

Adjusted in dosing regimen according to local protocol

Also known as: Hemlibra

Conventional dosing - open label; No intervention adjusted - open label

Eligibility Criteria

• Age: 1 Year+
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• Acquired haemophilia A

Sponsors & Collaborators

• Kathelijn Fischer: lead
• Erasmus Medical Center: collaborator
• Amsterdam University Medical Center: collaborator
• Leiden University Medical Center: collaborator
• Radboud University Medical Center: collaborator
• Maastricht University Medical Center: collaborator
• University Medical Center Groningen: collaborator
• HagaZiekenhuis: collaborator
• Dutch Society of Haemophilia Patients: collaborator

Study Sites (8)

Radboud University Medical Center

Nijmegen, Gelderland, 6525 GA, Netherlands

RECRUITING

Maastricht University Medical Center

Maastricht, Limburg, Netherlands

RECRUITING

Amsterdam University Medical Center

Amsterdam, North Holland, 1105 AZ, Netherlands

RECRUITING

Leids Universitair Medisch Centrum

Leiden, South Holland, 2300 RC, Netherlands

RECRUITING

Erasmus University Medical Center

Rotterdam, South Holland, 3000CA, Netherlands

RECRUITING

HagaZiekenhuis

The Hague, South Holland, 2545 CH, Netherlands

RECRUITING

University Medical Center Groningen

Groningen, 9700 RB, Netherlands

RECRUITING

University Medical Center Utrecht

Utrecht, Netherlands

RECRUITING

Related Publications (12)

• 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.

  PMID: 37369395 BACKGROUND

• 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.

  PMID: 34168126 BACKGROUND

• 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 BACKGROUND

• 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.

  PMID: 32744769 BACKGROUND

• 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.

  PMID: 33512413 BACKGROUND

• 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.

  PMID: 29214439 BACKGROUND

• 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.

  PMID: 32504271 BACKGROUND

• 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.

  PMID: 33709296 BACKGROUND

• 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.

  PMID: 34389928 BACKGROUND

• 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.

  PMID: 34970820 BACKGROUND

• 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.

  PMID: 36446746 BACKGROUND

• 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.

  PMID: 37029771 BACKGROUND

MeSH Terms

Conditions

Hemophilia A; Hemorrhage

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; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Study Officials Fischer, Dr, MD

  UMC Utrecht

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Kathelijn Fischer, Dr, MD.

CONTACT

+318 875 584 50; k.fischer@umcutrecht.nl

Konrad VD van der Zwet, MD

CONTACT

+31650124691; k.vanderzwet@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Model Details: * 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.

Study Record Dates

• First Submitted: February 28, 2024
• First Posted: March 20, 2024
• Study Start: September 8, 2022
• Primary Completion: March 1, 2026
• Study Completion (Estimated): August 1, 2026
• Last Updated: March 20, 2024

Record last verified: 2024-03

Data Sharing

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

Locations

NL (8)