CANADE Study

JRCT ID: jRCTs031210222

Registered date:04/08/2021

Basic Information

• Recruitment status: Not Recruiting
• Health condition(s) or Problem(s) studied: Congenital hemophilia A without factor VIII inhibitor
• Date of first enrollment: 16/08/2021
• Target sample size: 100
• Study type: Interventional

Intervention(s)

For treatment with emicizumab, follow the latest package insert, administer 3.0 mg / kg (body weight) subcutaneously once a week from the first dose to the fourth dose, and select one of the following from the fifth dose.
- 1.5 mg / kg (body weight), subcutaneously administered once a week
- 3.0 mg / kg (body weight), subcutaneously administered once every two weeks
- 6.0 mg / kg (body weight), subcutaneously administered once every 4 weeks
If regular factor VIII replacement therapy was given prior to the introduction of emicizumab, stop regular replacement therapy with factor VIII from the day of the second dose of emicizumab according to the package insert, but follow the policy of the doctor in charge and each institution.
Research participants will be examined once every three months to examine the presence or absence of bleeding, collect blood, and evaluate coagulation function during non-bleeding. Therefore, study participants in groups A and C will undergo five consultations and blood draws within one year of enrollment. For group B participants, the factor VIII preparation before the start of emicizumab (three blood draws at the time of consultation) and the first administration from the emicizumab introduction stage, 2 weeks, 3 or 4 weeks, and 3 thereafter. Monthly consultation and blood sampling (8 consultations and 10 blood sampling) are carried out.

Outcome(s)

Primary Outcome

Collective correlation and variability of emicizumab blood concentration and factor VIII activity using single measurement data in group A (continuous administration of emicizumab) and group C (group of factor VIII administration)
*1 Measure once in groups A and C by synthetic substrate method and TGA. For FVIII activity obtained by the synthetic substrate method using the core test (Note 1), the linear regression equation for the synthetic substrate method (Revohem Note 2): FVIII = beta1c x Emi + beta0c, for TGA, the linear regression equation FVIII = beta1t Estimate x Emi + beta0t respectively. Obtain the average value and 95% confidence interval of the coefficient beta1c and the constant beta0c in the synthetic substrate method and the coefficient beta1t and the constant beta0t in the TGA.
Note 1) The core test is a reagent for measuring factor VIII activity by the synthetic substrate method, and is widely used in Europe and the United States. Unlike the APTT coagulation one-step method, the measured value does not fluctuate depending on the type of factor VIII preparation, so it is optimal as the FVIII measured value in group C. Moreover, since it does not react with emicizumab, the coagulation effect of emicizumab cannot be evaluated, but only FVIII activity can be accurately measured even when FVIII is additionally administered under emicizumab administration. Therefore, it is also suitable for measuring FVIII activity in combination with FVIII in groups A and B (emicizumab administration group).
Note2) Revohem is also a reagent for measuring FVIII activity by the synthetic substrate method, and is covered by insurance in Japan. Since it reacts with emicizumab unlike the core test, it has been basically confirmed that the coagulation effect of emicizumab can be measured. In this study, Levohem is used to measure the coagulation effect of emicizumab in clinical specimens.

Secondary Outcome

1) Variation in correlation between blood concentration of emicizumab and factor VIII activity in the same individual by group B (newly introduced group of emicizumab) (individual difference)
*2 Blood will be collected at 3 points before and after administration of factor VIII and 3 points after administration of emicizumab. For the FVIII activity obtained by the synthetic substrate method using the core test, the linear regression equation: FVIII = beta1cn x Emi + beta0cn for the synthetic substrate method and the linear regression equation FVIII = beta1tn x Emi + beta0tn for TGA are estimated for each individual. Obtain the average value and 95% confidence interval of the coefficient beta1c and the constant beta0c in the synthetic substrate method and the coefficient beta1t and the constant beta0t in the TGA.
2) Correlation between factor VIII and peak thrombin in TGA using group C
*3 The synthetic substrate method has been established as a factor VIII activity measurement. In the previous paper, a linear correlation between factor VIII activity and peak thrombin was observed for TGA, and a linear correlation was basically confirmed under the TGA equipment and reagent conditions used in this study. Will be used to reassess the correlation between peak thrombin and FVIII.
3) Annual Bleeding Frequency (ABR)
Relationship between annual bleeding frequency (ABR) and synthetic substrate method, emicizumab blood level.
4) Evaluation of anti-emicizumab antibody
Evaluation of changes (increases) in TGA and synthetic substrate method due to additional administration of factor VIII with and without anti-emicizumab antibody
5) Hemostasis status and manifestation of diseases
Hemostasis status obtained from clinical symptoms and presence / absence of diseases including thromboembolism
6) Transition of general blood coagulation test
Evaluation of general coagulation tests (blood count, fibrinogen, FDP, D-dimer, PIC, TAT, SFMC) before and after administration of factor VIII

Key inclusion & exclusion criteria

• Age minimum: >= 20age old
• Age maximum: Not applicable
• Gender: Male

Include criteria

1)Inclusion criteria common to all patients (Group A, Group B, Group C)
- Male, agedover 20
- Patients with congenital severe hemophilia A without factor VIII inhibitors at the time of enrollment
(Severe: endogenous factor VIII activity <1%, inhibitor negative: inhibitor titer <0.6 BU / mL)
- Patients with a history of factor VIII administration at least 50 exposure days during bleeding or with routine replacement therapy
- Patients or the patient's legally authorized representative who have received sufficient explanation about this study and have voluntarily given their own consent in writing to participate in the study.
- Patients who can comply with the requirements and procedures for this study
2) Additional inclusion criteria in the continuous emicizumab administration group (group A)
- Patients receiving emicizumab continuously according to the dosing regimen described in the package insert for at least 12 weeks prior to enrollment
3) Additional inclusion criteria in the newly introduced emicizumab group (group B)
- In the treatment selection between the doctor and the patient, there are problems in the treatment of factor VIII preparations such as difficulty in home intravenous injection and frequent injections to stop bleeding, and emicizumab is an effective solution. Patients who are expected and wish to receive emicizumab.
Although there are no absolute criteria or conditions for the introduction of emicizumab, the Japanese Society for Thrombosis and Hemostasis, "Guidelines for Hemostasis Treatment for Hemostasis Patients 2019 Supplement" 10) states that "the convenience of subcutaneous injection is an advantage. Cases, cases with difficulty in intravenous injection and risk of bleeding, cases with low activity, etc. may be good indications, and factor VIII rather than emicizumab in cases with high activity or target joints. These are fully referred to.
4) Additional inclusion criteria in the factor VIII administration group (Group C)
- Patients receiving when bleeding or regular replacement therapy with factor VIII
- Patients who are not scheduled to introduce emicizumab for the next year at the time of enrollment

Exclude criteria

- Patients who have difficulty in visiting the hospital for the regular visits, during bleeding, or surgery / surgical procedures
- Patients diagnosed with bleeding disorders other than congenital hemophilia A
- Patients with abnormal liver function or platelet count at the time of screening (PT-INR> 1.2, AST / ALT level is 5 times or greater the upper limit of normal of the implementing medical institution, platelet count <100,000 / micro L)
- Patients with extremely difficult blood sampling procedure
- Patients who are judged by the principal investigator and/or the investigator to be inappropriate for the study

Related Information

• Primary Sponsor: Bingo Masato
• Source(s) of Monetary Support: Chugai Pharmaceutical Co., Ltd.