Child Clinical Trial
— DosEmiOfficial title:
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.
Status | Recruiting |
Enrollment | 95 |
Est. completion date | August 2026 |
Est. primary completion date | March 2026 |
Accepts healthy volunteers | No |
Gender | Male |
Age group | 1 Year and older |
Eligibility | 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 |
Country | Name | City | State |
---|---|---|---|
Netherlands | Amsterdam University Medical Center | Amsterdam | Noord-Holland |
Netherlands | HagaZiekenhuis | Den Haag | Zuid-Holland |
Netherlands | University Medical Center Groningen | Groningen | |
Netherlands | Leids Universitair Medisch Centrum | Leiden | Zuid-Holland |
Netherlands | Maastricht University Medical Center | Maastricht | Limburg |
Netherlands | Radboud University Medical Center | Nijmegen | Gelderland |
Netherlands | Erasmus University Medical Center | Rotterdam | Zuid-Holland |
Netherlands | University Medical Center Utrecht | Utrecht |
Lead Sponsor | Collaborator |
---|---|
Kathelijn Fischer | Amsterdam University Medical Center, Dutch Society of Haemophilia Patients, Erasmus Medical Center, HagaZiekenhuis, Leiden University Medical Center, Maastricht University Medical Center, Radboud University Medical Center, University Medical Center Groningen |
Netherlands,
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. — View Citation
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. — View Citation
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. — View Citation
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. Erratum In: Blood. 2023 Oct 12;142(15):1329. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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. Erratum In: Haemophilia. 2021 Jul;27(4):699. — View Citation
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. — View Citation
* Note: There are 12 references in all — Click here to view all references
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Proportion of patients without treated bleeds | Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing) | 12 months | |
Secondary | Proportion of patients without treated bleeds | Comparison proportion without treated bleeds 12 months before (conventional) and after intervention (PK-guided dosing) | 24 months | |
Secondary | Proportion of patients without spontaneous joint- or muscle bleeds | Comparison proportion without spontaneous joint- or muscle bleeds 6 and 12 months before and after intervention. | 24 months | |
Secondary | Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds | Comparison annualized bleeding rate 6 and 12 months before and after intervention. | 24 months | |
Secondary | To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab | 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 | |
Secondary | To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year. | Assessment of the cumulative number of sc. and/or iv. Injections related to coagulation correction. | 24 months | |
Secondary | To assess the performance of the population PK model | 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 | |
Secondary | To investigate whether direct joint health remains stable measured by physical examination when switching to lower-dosed emicizumab compared to conventional treatment | Joint status will be measured by physical examination (Haemophilia Joint Health Score; HJHS), | 12 months | |
Secondary | To investigate whether direct joint health remains stable measured by ultrasound when switching to lower-dosed emicizumab compared to conventional treatment | Joint status will be measured by ultrasound (if available, according to the HEAD US score). | 12 months | |
Secondary | To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment. | 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 | |
Secondary | To investigate if indirect joint health, as measured by biomarkers, remains stable when switching to lower doses of emicizumab compared to conventional treatment. | 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 | |
Secondary | To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab. | Health related quality of life will be assessed with EuroQol Five Dimensions Health Questionnaire (Youth) EQ5D(Y). | 12 months | |
Secondary | To investigate whether Health Related Quality of Life (HR-QoL) are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab. | Health related quality of life will be assed with PROMIS instruments (Physical Function/mobility and Pain Interference short forms). | 12 months | |
Secondary | To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab. | Sports participation (type, duration, frequency) will be assessed with Modifiable Activities Questionnaire (MAQ). | 12 months | |
Secondary | To investigate whether thrombin generation parameters can be used as a pharmacodynamic (PD) biomarker for emicizumab treatment efficacy. | To measure coagulation potential, blood samples will be collected to measure thrombin generation (Peak Height and ETP) | 12 months | |
Secondary | To assess and monitor pain during emicizumab administration | Assessment of pain during emicizumab administration by Visual Analogue Scale (scale 0-10) | 12 months |
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