E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a genetic deficiency of blood clotting factor VIII (FVIII), which causes increased bleeding |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10060612 |
E.1.2 | Term | Hemophilia A |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective 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. |
|
E.2.2 | Secondary objectives of the trial |
-% of patients without treated bleeds: 12M Clinical Phase+Bleeding Assessment Phase vs 12M PK-guided Dosing Phase+Dose Continuation Phase -% of patients with spontaneous joint/muscle bleeds: 6 and 12M Clinical Phase+Bleeding Assessment Phase vs 6 and 12M PK-guided Dosing Phase+Dose Continuation Phase -Annualized bleeding rate of treated bleeds, including joint/sports-induced bleeds: 6M Bleeding Assessment Phase vs6M PK-Guided Dosing Phase -Annualized bleeding rate of treated bleeds, including joint/sports-induced bleeds: 6M retrospective + 6M prospective data (Clinical Phase+Bleeding Assessment Phase) vs12M prospective data of PK guided dosing (PK-guided Dosing Phase+Dose Continuation Phase) -Cost-effectiveness between 6M of conventional dosing (Bleeding Assessment Phase) vs 6M of individualized PK-guided dosing (PK-Guided Dosing Phase) -Performance of MAP Bayesian procedure -Joint status -QoL -Pain at emicizumab administration -Sports participation -Coagulation potential |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Confirmed diagnosis of congenital haemophilia A, with a baseline endogenous FVIII of <6 IU/mL; - Aged > 1 year at inclusion - Receiving conventional dosing of emicizumab (6 mg/kg/4 weeks with varying intervals) for a duration of at least 6 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
|
|
E.4 | Principal exclusion criteria |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome parameter is bleeding, defined as: Proportion of patients without treated bleeds (6 months Bleeding Assessment Phase versus 6 months PK-Guided Dosing Phase).
|
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
All endpoints will be assessed at the end of follow-up time (6 months after intervention). |
|
E.5.2 | Secondary end point(s) |
The secondary outcomes are defined as: - Proportion of patients without treated bleeds (12 months Clinical Phase+Bleeding Assessment Phase versus 12 months PK-guided Dosing Phase+Dose Continuation Phase) - 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). - 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). - 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). - 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): o 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. o 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). - 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 LC-MS/MS. [24] - 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. - 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). - Assessment of pain during emicizumab administration by Visual Analogue Scale (VAS). - Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ). - Plasma coagulation potential will be measured with thrombin generation tests as a potential read-out for pharmacodynamics. |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
All endpoints will be assessed at the end of follow-up time (6 and 12 months after intervention). |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |