Hemophilia A With InhibitorPhase 4DosEmiNCT06320626
Pharmacokinetic-guided Dosing of Emicizumab
A Phase 4 study testing Emicizumab - PK-guided dose reduction, Emicizumab - Dosis continuation group and Emicizumab - Dose adjustment group in people with Hemophilia A With Inhibitor and Hemophilia A Without Inhibitor, run by Kathelijn Fischer at 8 sites in Netherlands.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 1 year and older, men only
- Conditions the study is for
- Hemophilia A With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia A, Severe
- What is being tested?
- Emicizumab - PK-guided dose reduction, Emicizumab - Dosis continuation group and Emicizumab - Dose adjustment group
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 95 participants
- Where
- 8 sitesNetherlands
- Study dates
- 8 Sep 2022to Aug 2026
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 1 year and older
- Men only
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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
Who cannot join
- Acquired haemophilia A
Trial locations and contacts
8 sites in 1 country.
8 sites in 1 country
Netherlands8 sites, 8 recruiting
- Recruiting
Amsterdam University Medical Center
Amsterdam, North Holland, 1105 AZ
Michiel Coppens, Dr, MD, +31(0)20 566 5964, m.coppens@amsterdamumc.nl
Michiel Coppens, Dr, MD
- Recruiting
University Medical Center Groningen
Groningen, 9700 RB
Louise Hooimeijer, MD, +310-503612740, h.l.hooimeijer@umcg.nl
Louise Hooimeijer, MD
- Recruiting
Leids Universitair Medisch Centrum
Leiden, South Holland, 2300 RC
Paul den Exter, Dr, MD, +31 (0)71 526 1850, p.l.den_exter@lumc.nl
Paul den Exter, Dr, MD
- Recruiting
Maastricht University Medical Center
Maastricht, Limburg
Floor Moenen, Dr, MD, +31433876543, floor.moenen@mumc.nl
Floor Moenen, Dr, MD
- Recruiting
Radboud University Medical Center
Nijmegen, Gelderland, 6525 GA
Saskia Schols, Dr, MD, +310 24 361 8823, Saskia.Schols@radboudumc.nl
Saskia Schols, Dr, MD
- Recruiting
Erasmus University Medical Center
Rotterdam, South Holland, 3000CA
Marjon Cnossen, Dr., MD, +31107040113, m.cnossen@erasmusmc.nl
Marjon Cnossen, Dr. MD
- Recruiting
HagaZiekenhuis
The Hague, South Holland, 2545 CH
Paula Ypma, MD, +310702102620, haematologie@hagaziekenhuis.nl
Paula Ypma, MD
- Recruiting
University Medical Center Utrecht
Utrecht
Kathelijn Fischer, Dr, MD, +31887558450, K.Fischer@umcutrecht.nl
Konrad van der Zwet, MD, +31650124691, dosemi@umcutrecht.nl
About this study
Official 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.
Read the 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.
- Conditions
- Hemophilia A With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia A, Severe, Adolescent, Child, Adult
- Being tested
- Emicizumab - PK-guided dose reduction, Emicizumab - Dosis continuation group, Emicizumab - Dose adjustment group
- Keywords
- Emicizumab, Hemophilia A, Monoclonal antibodies, PK-guided dosing, Hemorrhage
- Medical subject headings
- Hemophilia A, Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Emicizumab - PK-guided dose reductionOther
Also called Hemlibra
PK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL.
Emicizumab - Dosis continuation groupOther
Also called Hemlibra
Continue on their current dose regimen
Emicizumab - Dose adjustment groupOther
Also called Hemlibra
Adjusted in dosing regimen according to local protocol
| Study group | Role | What they receive |
|---|---|---|
| Conventional dosing - open label | Other | Patients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing. Receives: Other: Emicizumab - PK-guided dose reduction; Other: Emicizumab - Dosis continuation group; Other: Emicizumab - Dose adjustment group |
| PK-guided dosing - open label | Other | 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. Receives: Other: Emicizumab - PK-guided dose reduction |
| No intervention continuation - open label | Other | 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. Receives: Other: Emicizumab - Dosis continuation group |
| No intervention adjusted - open label | Other | 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. Receives: Other: Emicizumab - Dose adjustment group |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients without treated bleeds
Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)
Measured: 12 months
Secondary outcomes (15)
Proportion of patients without treated bleeds
Comparison proportion without treated bleeds 12 months before (conventional) and after intervention (PK-guided dosing)
Measured: 24 months
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.
Measured: 24 months
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.
Measured: 24 months
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).
Measured: 24 months
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.
Measured: 24 months
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.
Measured: 12 months
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),
Measured: 12 months
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).
Measured: 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.
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.
Measured: 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.
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.
Measured: 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.
Health related quality of life will be assessed with EuroQol Five Dimensions Health Questionnaire (Youth) EQ5D(Y).
Measured: 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.
Health related quality of life will be assed with PROMIS instruments (Physical Function/mobility and Pain Interference short forms).
Measured: 12 months
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).
Measured: 12 months
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)
Measured: 12 months
To assess and monitor pain during emicizumab administration
Assessment of pain during emicizumab administration by Visual Analogue Scale (scale 0-10)
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted20 Mar 2024
- Study start8 Sep 2022
- Primary completionMar 2026 (estimated)
- Study completionAug 2026 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Hemophilia A With InhibitorStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Model description
- * PK-guided dosing - Intervention group (12M): Subjects with emicizumab concentration of ≥ 40 μg/mL will receive individualized PK-guided dose reduction of emicizumab targeted at a Ctrough of 30μg/mL. The validated population PK model is based on published population PK and PK/PD modelling studies. (9,10,15) * PK-Guided dosing - Non-intervention group (12M): Subjects with emicizumab concentration of 25-39 μg/mL will continue on their current dose regimen and will be followed according to the same assessment schedule as the Intervention Group. Only subjects with emicizumab plasma concentration \< 25 μg/mL will be adjusted in dosing regimen according to local protocol. These subjects will be followed for selective safety data only.
- Masking
- None (open label)
- Enrolment
- 95 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Kathelijn Fischer
- Sponsor type
- University, hospital or other
- Collaborators
- Erasmus Medical Center, Amsterdam University Medical Center, Leiden University Medical Center, Radboud University Medical Center, Maastricht University Medical Center, University Medical Center Groningen, HagaZiekenhuis, Dutch Society of Haemophilia Patients
- Responsible party
- Sponsor-investigator, Kathelijn Fischer, UMC Utrecht
- Investigators
- Study Officials Fischer, Dr, MD, Principal investigator, UMC Utrecht
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06320626
- Sponsor's protocol ID
- 22-571
- Acronym
- DosEmi
- Status last verified
- Mar 2024
- First submitted
- 28 Feb 2024
- Last updated
- 20 Mar 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes
Publications
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.
PubMed 37369395Berntorp 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.
PubMed 34168126Blanchette 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.
PubMed 25059285Srivastava 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.
PubMed 32744769Callaghan 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.
PubMed 33512413Yoneyama 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.
PubMed 29214439Retout 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.
PubMed 32504271Jonsson 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.
PubMed 33709296Donners 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.
PubMed 34389928Lehtinen 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.
PubMed 34970820Chuansumrit 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.
PubMed 36446746Bansal 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.
PubMed 37029771
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pharmacokinetic-guided Dosing of Emicizumab in Congenital Haemophilia A Patients - The DosEmi Study
- ClinicalTrials.gov ID
- NCT06320626
- Acronym / sponsor ID
- DosEmi / 22-571
- Conditions
- Hemophilia A With Inhibitor, Hemophilia A Without Inhibitor, Hemophilia A, Severe, Adolescent, Child, Adult
- Keywords
- Emicizumab, Hemophilia A, Monoclonal antibodies, PK-guided dosing, Hemorrhage
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 95 participants (estimated)
- Lead sponsor
- Kathelijn FischerUniversity, hospital or other
- Collaborators
- Erasmus Medical Center, Amsterdam University Medical Center, Leiden University Medical Center, Radboud University Medical Center, Maastricht University Medical Center, University Medical Center Groningen, HagaZiekenhuis, Dutch Society of Haemophilia Patients
- Study start
- 8 Sep 2022 (actual)
- Primary completion
- Mar 2026 (estimated)
- Study completion
- Aug 2026 (estimated)
- First posted
- 20 Mar 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Crossover
- Masking
- None (open label)
- Number of arms
- 4
- Model description
- * PK-guided dosing - Intervention group (12M): Subjects with emicizumab concentration of ≥ 40 μg/mL will receive individualized PK-guided dose reduction of emicizumab targeted at a Ctrough of 30μg/mL. The validated population PK model is based on published population PK and PK/PD modelling studies. (9,10,15) * PK-Guided dosing - Non-intervention group (12M): Subjects with emicizumab concentration of 25-39 μg/mL will continue on their current dose regimen and will be followed according to the same assessment schedule as the Intervention Group. Only subjects with emicizumab plasma concentration < 25 μg/mL will be adjusted in dosing regimen according to local protocol. These subjects will be followed for selective safety data only.
| Arm | Type | Receives |
|---|---|---|
| Conventional dosing - open label | Other | Other: Emicizumab - PK-guided dose reduction, Other: Emicizumab - Dosis continuation group, Other: Emicizumab - Dose adjustment groupPatients will be followed 6 months retrospectively and 6 months prospectively on conventional dosing. |
| PK-guided dosing - open label | Other | Other: Emicizumab - PK-guided dose reductionPatients 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. |
| No intervention continuation - open label | Other | Other: Emicizumab - Dosis continuation groupPatients 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. |
| No intervention adjusted - open label | Other | Other: Emicizumab - Dose adjustment groupPatients 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. |
Who may qualify
- Ages
- 1 year and older
- Sex
- Male only
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (8 listed)
- 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.
Key exclusion criteria (1 listed)
- Acquired haemophilia A
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Emicizumab - PK-guided dose reductionAlso: HemlibraPK-guided dose reduction emicizumab targeted at a Ctrough of 30μg/mL. | Other | Conventional dosing - open label, PK-guided dosing - open label |
| Emicizumab - Dosis continuation groupAlso: HemlibraContinue on their current dose regimen | Other | Conventional dosing - open label, No intervention continuation - open label |
| Emicizumab - Dose adjustment groupAlso: HemlibraAdjusted in dosing regimen according to local protocol | Other | Conventional dosing - open label, No intervention adjusted - open label |
Primary outcome
Proportion of patients without treated bleeds
Time frame: 12 months
Comparison proportion treated bleeds 6 months before (conventional) and after intervention (PK-guided dosing)
15 secondary outcomes
Proportion of patients without treated bleeds
Time frame: 24 months
Proportion of patients without spontaneous joint- or muscle bleeds
Time frame: 24 months
Annualized bleeding rate (ABR) of treated bleeds, including joint bleeds and sport-induced bleeds
Time frame: 24 months
To compare cost-effectiveness between conventional dosing and individualized PK-guided dosing of emicizumab
Time frame: 24 months
To assess the cumulative number of coagulation factor (sc. and/or iv.) of per year.
Time frame: 24 months
To assess the performance of the population PK model
Time frame: 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
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
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
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
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
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
To investigate whether sports participation are similar in patients receiving conventional dosing compared with PK-guided dosing of emicizumab.
Time frame: 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 assess and monitor pain during emicizumab administration
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2024.
- Background: PubMed 37369395Donners 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.
- Background: PubMed 34168126Berntorp 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.
- Background: PubMed 25059285Blanchette 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.
- Background: PubMed 32744769Srivastava 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.
- Background: PubMed 33512413Callaghan 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.
- Background: PubMed 29214439Yoneyama 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.
- Background: PubMed 32504271Retout 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.
- Background: PubMed 33709296Jonsson 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.
- Background: PubMed 34389928Donners 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.
- Background: PubMed 34970820Lehtinen 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.
- Background: PubMed 36446746Chuansumrit 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.
- Background: PubMed 37029771Bansal 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.
- Individual participant dataSharing planned: Yes
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Study Officials Fischer, Dr, MD principal investigator
UMC Utrecht
8 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Emicizumab - PK-guided dose reduction, Emicizumab - Dosis continuation group and Emicizumab - Dose adjustment group in people with Hemophilia A With Inhibitor and Hemophilia A Without Inhibitor, run by Kathelijn Fischer at 8 sites in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 20 Mar 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 8 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Kathelijn Fischer, Dr, MD. (+318 875 584 50, k.fischer@umcutrecht.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Proportion of patients without treated bleeds (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06320626, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2024.