Clinical trial • Phase IV • Haematology

Emicizumab for Congenital Haemophilia A

Phase IV trial of Emicizumab for Congenital Haemophilia A.

Overview

Trial Therapeutic Area: Haematology
Trial Disease: Congenital Haemophilia A
Trial Stage: Phase IV
Drug Modality: Monoclonal antibody
Paediatric Trial: Yes

Key dates

Initial CTIS Submission Date: 18-06-2024
First CTIS Authorization Date: 28-06-2024

Trial design

open-label, conventional dosing of emicizumab (described as 6 mg/kg every 4 weeks with varying intervals) versus pk-guided dosing (dose reduction aiming for target trough ctrough between 25 - 35 µg/ml using a pk model); patients with low concentrations (<25 µg/ml) may have dose increased by treating physician.-controlled, adaptive Phase IV trial across 8 sites in Netherlands.

Open Label: Yes
Comparator: Conventional dosing of emicizumab (described as 6 mg/kg every 4 weeks with varying intervals) versus PK-guided dosing (dose reduction aiming for target trough Ctrough between 25 - 35 µg/mL using a PK model); patients with low concentrations (<25 µg/mL) may have dose increased by treating physician.
Adaptive: True, allocation and dosing are adaptive based on measured emicizumab plasma concentration: patients are allocated into groups by concentration (≥40 µg/mL -> dose reduction to target trough 25-35 µg/mL; 25-40 µg/mL -> dose continuation; <25 µg/mL -> dose increase by treating physician and excluded from further study visits). Dose adjustments follow a population PK/MAP Bayesian procedure described in the protocol.
Biomarker Stratified: True, biomarker: emicizumab plasma concentration; strata: ≥40 µg/mL; 25-40 µg/mL; <25 µg/mL
Single Multiple Or Escalation Dose Combined: Yes
Target Sample Size: 135
Trial Duration For Participant: 548

Eligibility

Recruits 135 paediatric patients.

Vulnerable Population: Minors are included (age >1 year). Informed consent must be provided in writing either by the subject or by the parents/legal guardian. Age-specific subject information and informed consent forms (ICFs) are present: adult ICF, ICF for 12-15 years, ICF for under 12 years, and ICFs for parents/caregivers (documents listed in CTIS).

Inclusion criteria

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

Exclusion criteria

{"criterion_text":"- Acquired haemophilia A"}

Endpoints

Primary endpoints

{"endpoint_text":"- Proportion of patients without treated bleeds (6 months Bleeding Assessment Phase versus 6 months PK-Guided Dosing Phase).","definition_or_measurement_approach":"Proportion of patients without treated bleeds comparing the 6-month Bleeding Assessment Phase (conventional dosing) versus the 6-month PK-Guided Dosing Phase."}

Secondary endpoints

{"endpoint_text":"- Proportion of patients without treated bleeds (12 months Clinical Phase+Bleeding Assessment Phase versus 12 months PK-guided Dosing Phase+Dose Continuation Phase)","definition_or_measurement_approach":"Proportion without treated bleeds comparing 12 months on conventional dosing versus 12 months on PK-guided dosing/continuation."}
{"endpoint_text":"- 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).","definition_or_measurement_approach":"Proportion with spontaneous joint or muscle bleeds at 6 and 12 months comparing phases."}
{"endpoint_text":"- 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).","definition_or_measurement_approach":"ABR of treated bleeds (including joint and sports-induced bleeds) comparing 6-month periods."}
{"endpoint_text":"- 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).","definition_or_measurement_approach":"ABR comparison using 6 months retrospective + 6 months prospective conventional dosing data versus 12 months prospective PK-guided dosing data."}
{"endpoint_text":"- 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","definition_or_measurement_approach":"Health economic comparison of conventional dosing versus individualized PK-guided dosing over specified periods (details in protocol)."}
{"endpoint_text":"- 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","definition_or_measurement_approach":"Performance measured as % patients within ±20% of target or within 25-39 µg/mL; plasma levels measured by LC-MS/MS at UMC Utrecht."}
{"endpoint_text":"- 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.","definition_or_measurement_approach":"Joint status assessed by HJHS, optional ultrasound (HEAD-US) and biochemical biomarkers of bone/cartilage turnover."}
{"endpoint_text":"- 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).","definition_or_measurement_approach":"HR-QoL assessed using EQ-5D(Y) and PROMIS instruments (specified short forms)."}
{"endpoint_text":"- Assessment of pain during emicizumab administration by Visual Analogue Scale (VAS).","definition_or_measurement_approach":"Pain during administration measured by VAS."}
{"endpoint_text":"- Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction.","definition_or_measurement_approach":"Count of cumulative subcutaneous and/or IV injections for coagulation correction per year."}
{"endpoint_text":"- Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ).","definition_or_measurement_approach":"Sports participation measured by MAQ (type, duration, frequency)."}
{"endpoint_text":"- Plasma coagulation potential will be measured with thrombin generation tests as a potential read-out for pharmacodynamics.","definition_or_measurement_approach":"Pharmacodynamic PD measure via thrombin generation tests."}

Recruitment

Planned Sample Size: 135
Recruitment Window Months: 45
Consent Approach: Written informed consent is required from the subject or from the parents/legal guardian. Age-specific information and consent forms are provided: adult ICF, ICF for 12-15 years, ICF for under 12 years, and ICFs for parents/caregivers (documents in CTIS list). Documents available in Dutch (nl-NL) as indicated by document filenames.

Geography

Total Number Of Sites: 8
Total Number Of Participants: 135

Netherlands

Earliest CTIS Part Ii Submission Date: 27-06-2024
Latest Decision Or Authorization Date: 11-02-2026
Processing Time Days: 595
Number Of Sites: 8
Number Of Participants: 135

Sites

Site Name: Stichting Radboud universitair medisch centrum
Department Name: Hematology
Contact Person Name: Saskia E.M Schols
Contact Person Email: rtcclinicalstudies@radboudumc.nl

Site Name: Leids Universitair Medisch Centrum (LUMC)
Department Name: Internal Medicine - Thrombosis and Hemostasis
Contact Person Name: Paul L. den Exter
Contact Person Email: grp@lumc.nl

Site Name: Erasmus Universitair Medisch Centrum Rotterdam (Erasmus MC)
Department Name: Pediatric Hematology
Contact Person Name: Marjon. H. Cnossen
Contact Person Email: ctis@erasmusmc.nl

Site Name: Universitair Medisch Centrum Groningen
Department Name: Pediatrics
Contact Person Name: Hélène L. Hooimeijer
Contact Person Email: researchsupport@umcg.nl

Site Name: Haga Hospital
Department Name: Internal Medicine - hematology
Contact Person Name: Paula F. Ypma
Contact Person Email: d.houtsma@hagaziekenhuis.nl

Site Name: Academisch Ziekenhuis Maastricht
Department Name: Hematology
Contact Person Name: Floor C.J.I. Heubel-Moenen
Contact Person Email: submissions.CTCM@mumc.nl

Site Name: Stichting Amsterdam UMC
Department Name: Vascular Medicine
Contact Person Name: Michiel Coppens
Contact Person Email: ctis@amsterdamumc.nl

Site Name: Universitair Medisch Centrum Utrecht
Department Name: Van Creveldkliniek
Contact Person Name: Corien Eckhardt
Contact Person Email: ctis@umcutrecht.nl

Sponsor

Primary sponsor

Full Name: Universitair Medisch Centrum Utrecht
Organisation Type: Hospital/Clinic/Other health care facility
Country Of Registered Address: Netherlands

Investigational products

Investigational Product Name: Hemlibra 150 mg/mL solution for injection
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 105 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

Investigational Product Name: Hemlibra 30 mg/mL solution for injection
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 30 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

Investigational Product Name: Hemlibra 30 mg/mL solution for injection (IS authorisation variant)
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 12 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

Investigational Product Name: Hemlibra 150 mg/mL solution for injection (suspension for injection variant)
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 300 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

Investigational Product Name: Hemlibra 150 mg/mL solution for injection (other authorised pack variant)
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 60 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

Investigational Product Name: Hemlibra 150 mg/mL solution for injection (additional authorised pack variant)
Active Substance: Emicizumab
Modality: Monoclonal antibody
Routes Of Administration: Subcutaneous injection
Route: Subcutaneous injection
Authorisation Status: Authorised
Starting Dose: 6 mg/kg every 4 weeks (conventional dosing)
Frequency: Every 4 weeks; PK-guided adjustments per protocol
Maximum Dose: 150 mg
Dose Escalation Increase: Initial: 6 mg/kg/4 weeks; subsequent doses adjusted per PK-model by treating physician (no specific fixed mg increments stated)

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