Pharmacokinetic-guided Dosing of Emicizumab (DosEmi)

March 12, 2024 updated by: Kathelijn Fischer

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

95

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Netherlands
      • Groningen, Netherlands, 9700 RB
        • Recruiting
        • University Medical Center Groningen
        • Contact:
        • Sub-Investigator:
          • Louise Hooimeijer, MD
      • Utrecht, Netherlands
        • Recruiting
        • University Medical Center Utrecht
        • Contact:
        • Contact:
        • Principal Investigator:
          • Kathelijn Fischer, Dr, MD
        • Sub-Investigator:
          • Konrad van der Zwet, MD
        • Sub-Investigator:
          • Lize F.D. van Vulpen, Dr, MD
        • Sub-Investigator:
          • Roger E.G. Schutgens, Prof, MD
        • Sub-Investigator:
          • Paul van der Valk, MD
        • Sub-Investigator:
          • Karin P.M. van Galen, Dr, MD
        • Sub-Investigator:
          • Nanda Uitslager, Msc
    • Gelderland
      • Nijmegen, Gelderland, Netherlands, 6525 GA
        • Recruiting
        • Radboud University Medical Center
        • Contact:
        • Sub-Investigator:
          • Saskia Schols, Dr, MD
    • Limburg
      • Maastricht, Limburg, Netherlands
        • Recruiting
        • Maastricht University Medical Center
        • Contact:
        • Sub-Investigator:
          • Floor Moenen, Dr, MD
    • Noord-Holland
      • Amsterdam, Noord-Holland, Netherlands, 1105 AZ
        • Recruiting
        • Amsterdam University Medical Center
        • Contact:
        • Sub-Investigator:
          • Michiel Coppens, Dr, MD
    • Zuid-Holland
      • Den Haag, Zuid-Holland, Netherlands, 2545 CH
        • Recruiting
        • HagaZiekenhuis
        • Contact:
        • Sub-Investigator:
          • Paula Ypma, MD
      • Leiden, Zuid-Holland, Netherlands, 2300 RC
        • Recruiting
        • Leids Universitair Medisch Centrum
        • Contact:
        • Sub-Investigator:
          • Paul den Exter, Dr, MD
      • Rotterdam, Zuid-Holland, Netherlands, 3000CA
        • Recruiting
        • Erasmus University Medical Center
        • Contact:
        • Sub-Investigator:
          • Marjon Cnossen, Dr. MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Crossover Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Other: Conventional dosing - open label
Patients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing.
Other: Emicizumab - PK-guided dose reduction
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Other Names:
  • Hemlibra
Other: Emicizumab - Dosis continuation group
Continue on their current dose regimen
Other Names:
  • Hemlibra
Other: Emicizumab - Dose adjustment group
Adjusted in dosing regimen according to local protocol
Other Names:
  • Hemlibra
Other: 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.
Other: Emicizumab - PK-guided dose reduction
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Other Names:
  • Hemlibra
Other: 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.
Other: Emicizumab - Dosis continuation group
Continue on their current dose regimen
Other Names:
  • Hemlibra
Other: 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.
Other: Emicizumab - Dose adjustment group
Adjusted in dosing regimen according to local protocol
Other Names:
  • Hemlibra

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients without treated bleeds
Time Frame: 12 months
Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)
12 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Proportion of patients without treated bleeds
Time Frame: 24 months
Comparison proportion without treated bleeds 12 months before (conventional) and after intervention (PK-guided dosing)
24 months
Proportion of patients without spontaneous joint- or muscle bleeds
Time Frame: 24 months
Comparison proportion without spontaneous joint- or muscle bleeds 6 and 12 months before and after intervention.
24 months
Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds
Time Frame: 24 months
Comparison annualized bleeding rate 6 and 12 months before and after intervention.
24 months
To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab
Time Frame: 24 months
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
To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.
Time Frame: 24 months
Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction.
24 months
To assess the performance of the population PK model
Time Frame: 12 months
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
To investigate whether direct joint health remains stable measured by physical examination when switching to lower-dosed emicizumab compared to conventional treatment
Time Frame: 12 months
Joint status will be measured by physical examination (Haemophilia Joint Health Score; HJHS),
12 months
To investigate whether direct joint health remains stable measured by ultrasound when switching to lower-dosed emicizumab compared to conventional treatment
Time Frame: 12 months
Joint status will be measured by ultrasound (if available, according to the HEAD US score).
12 months
To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
Time Frame: 12 months
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
To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment.
Time Frame: 12 months
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
To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Time Frame: 12 months
Health related quality of life will be assessed with EuroQol Five Dimensions Health Questionnaire (Youth) EQ5D(Y).
12 months
To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Time Frame: 12 months
Health related quality of life will be assed with PROMIS instruments (Physical Function/mobility and Pain Interference short forms).
12 months
To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Time Frame: 12 months
Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ).
12 months
To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy.
Time Frame: 12 months
To measure coagulation potential, blood samples will be collected to measure thrombin generation (Peak Height and ETP)
12 months
To assess and monitor pain during emicizumab administration
Time Frame: 12 months
Assessment of pain during emicizumab administration by Visual Analogue Scale (scale 0-10)
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Kathelijn Fischer

Collaborators

Radboud University Medical Center
University Medical Center Groningen
Maastricht University Medical Center
Erasmus Medical Center
Leiden University Medical Center
HagaZiekenhuis
Amsterdam University Medical Center
Dutch Society of Haemophilia Patients

Investigators

  • Principal Investigator: Study Officials Fischer, Dr, MD, UMC Utrecht

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 8, 2022

Primary Completion (Estimated)

March 1, 2026

Study Completion (Estimated)

August 1, 2026

Study Registration Dates

First Submitted

February 28, 2024

First Submitted That Met QC Criteria

March 12, 2024

First Posted (Actual)

March 20, 2024

Study Record Updates

Last Update Posted (Actual)

March 20, 2024

Last Update Submitted That Met QC Criteria

March 12, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 22-571

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • SAP

Study Data/Documents

  1. Study Protocol
    Information identifier: 37369395
    Information comments: Published study protocol

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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