Pharmacokinetic-guided dosing of emicizumab in congenital haemophilia A patients – The DosEmi study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Utrecht

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

8 Sep 2022 → ongoing

Decision date (initial)

2024-06-28

Transition trial

Yes

Low-intervention

Yes

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GIDS program NFU & Zorgverzekeraars Nederland

External identifiers

EU CT number

2024-515528-35-00

EudraCT number

2021-004039-10

ClinicalTrials.gov

NCT06320626

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Pharmacokinetic, Therapy

To determine whether individualized pharmacokinetic (PK)-guided dosing of emicizumab is non-inferior to conventional dosing of emicizumab in the prevention of treated
bleeds, spontaneous joint- or muscle bleeds, and overall bleeding in patients with congenital haemophilia A.

Secondary objectives 10

1. Proportion of patients without treated bleeds (12 months before and after intervention)
2. Proportion of patients without spontaneous joint- or muscle bleeds (6 and 12 months before and after intervention)
3. Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sports induced bleeds (6 and 12 months before and after intervention).
4. To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab
5. To assess the performance of the population PK model
6. To investigate whether joint health remains stable when switching to lower-dosed emicizumab treatment
7. To investigate whether Health Related Quality of Life (HR-QoL) and sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab
8. To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy
9. To assess and monitor pain during emicizumab administration
10. To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.

Conditions and MedDRA coding

Congenital Haemophilia A

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Confirmed diagnosis of congenital haemophilia A, with a baseline endogenous FVIII of <6 IU/mL;
2. Aged > 1 year at inclusion
3. Receiving conventional dosing of emicizumab (6 mg/kg/4 weeks with varying intervals) for a duration of at least 12 months prior to inclusion;
4. 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.
5. Willing and able to provide written informed consent, either by the subject or its parents/legal guardian
6. Willing to provide bleeding assessment information
7. Willing to adhere to the medication regimen

Exclusion criteria 1

1. Acquired haemophilia A

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Proportion of patients without treated bleeds (6 months Bleeding Assessment Phase versus 6 months PK-Guided Dosing Phase).

Secondary endpoints 12

1. Proportion of patients without treated bleeds (12 months Clinical Phase+Bleeding Assessment Phase versus 12 months PK-guided Dosing Phase+Dose Continuation Phase)
2. Proportion of patients with spontaneous joint- or muscle bleeds (6 and 12 months Clinical Phase+Bleeding Assessment Phase versus 6 and 12 months PK-guided Dosing Phase+Dose Continuation Phase).
3. Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sports induced bleeds (6 months Bleeding Assessment Phase versus 6 months PK-Guided Dosing Phase).
4. Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sports induced bleeds (6 months retrospective + 6 months prospective data (Clinical Phase+Bleeding Assessment Phase) versus 12 months prospective data of PK guided dosing (PK-guided Dosing Phase+Dose Continuation Phase).
5. Cost-effectiveness between 6 months of conventional dosing (Bleeding Assessment Phase) and 6 months of individualized PK-guided dosing of emicizumab (PK-Guided Dosing Phase), further details see protocol
6. 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. All emicizumab plasma levels will be determined in the laboratory of the University Medical Center Utrecht using a specifically developed LCMS/MS
7. Joint status as measured by physical examination (Haemophilia Joint Health Score; HJHS), ultrasound (if available, according to the HEAD US score) and biomarkers of bone and cartilage turnover.
8. Health related quality of life will be assessed with EQ5D(Y) (5 questions), and PROMIS instruments (Physical Function/mobility and Pain Interference short forms) (8 questions each).
9. Assessment of pain during emicizumab administration by Visual Analogue Scale (VAS).
10. Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction.
11. Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ).
12. Plasma coagulation potential will be measured with thrombin generation tests as a potential read-out for pharmacodynamics.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Utrecht

Sponsor organisation

Universitair Medisch Centrum Utrecht

Address

Heidelberglaan 100

City

Utrecht

Postcode

3584 CX

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Corien Eckhardt

Public contact point

Organisation

Universitair Medisch Centrum Utrecht

Contact name

Corien Eckhardt

Locations

1 EU/EEA country · 8 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 23 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications