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Assessment of global coagulation function under treatment of emicizumab concomitant with bypassing
agents in hemophiliaA with inhibitor

UNEBI Study

38

Baseline background characteristics for the full study population and the efficacy analysis population (participants in the study who had events only, Full Analysis Set; FAS) are shown below (summarized as median [minimum, maximum] or frequency (%)). Full study population N=38 Age: 25 [7, 67]. Factor 8 inhibitor level: 3.5 [0.0, 2191.2]. History of emicizumab use (months): 44[0, 89] Hemophilia A severity: Mild (>=5%): 3 (7.9%) Moderate (1-5%): 3 (7.9%) Severe (<1%): 32 (84.2%) Bypass drug use to date FEIBA: 30 (78.9%) NovoSeven: 34 (89.5%) Byclot: 6 (15.8%) Others: 15 (39.5%) Efficacy analysis population (FAS) N=18 Age: 27[7, 61] Factor 8 inhibitor level: 3.0 [0.4, 121.2]. History of emicizumab use (months): 46[1, 89] Hemophilia A severity: Mild (>=5%): 0 (0.0%) Moderate (1-5%): 2 (11.1%) Severe (<1%): 16 (88.9%) Bypass drug use to date FEIBA 13 (72.2%) NovoSeven: 14 (77.8%) Byclot: 3 (16.7%) Others: 6 (33.3%)

2020/03/19: Date of first participant enrollment 2020/03/24: Date of first event 2022/09/30: Date of last event 2023/03/13: Date of last visit

In the safety analysis population (overall study participant population, N=38), the incidence of adverse events after study enrollment was 2.6% (1 case, 2 events), and there were 0 events for which a causal relationship to the study drug (emicizumab) could not be ruled out. The incidence of serious adverse events was 2.6% (1 case, 1 event). Details of serious adverse events are given below. no AESI were occurred. Serious adverse events Infectious cholecystitis (1 case, 2.6%, no causal relationship)

Analyses for bleeding events included only first-ever events for each study participant (First Event Analysis Set; FEAS). Primary endpoint The mean [95% confidence interval (95%CI)] of the "Degree of improvement in maximum coagulation rate by coagulation waveform analysis before and after administration of fixed-dose bypass hemostatic agents" ranged from 5.63 [5.25 to 6.00] (before administration) to 6.33 [6.01 to 6.65] (after administration). Relative to the Nara Medical University Hospital Institutional Reference Value (0%, 4.49*; 100%, 7.51), the relative values ranged from 37.6% [25.2% to 49.9%] (before administration) to 60.9% [50.2% to 71.5%] (after administration). * Reference value for 0% was the mean value of all samples in regular visit (n=93) with addition of anti-emicizumab antibody. Secondary endpoint 1. Comparative evaluation with and without addition of anti-emicizumab antibody for changes of comprehensive coagulation parameter before and after administration of bypass hemostatic agents The mean [95%CI] of the maximum coagulation velocity with anti-emicizumab antibody addition ranged from 4.57 [4.32 to 4.83] (before administration) to 6.18 [5.86 to 6.49] (after administration) (without anti-emicizumab antibody addition, the results are the same as for the primary endpoint). The relative response rate was 2.7% [-5.7% to 11.2%] (before administration) to 55.8% [45.4% to 66.2%] (after administration) when relative to the institutional reference value of Nara Medical University Hospital (0%, 4.49; 100%, 7.51). (without anti-emicizumab antibody addition, the results are the same as for the primary endpoint). 2. Efficacy evaluation of emicizumab with and without addition of anti-emicizumab antibody using comprehensive coagulation tests in regular samples The mean [95%CI] maximum coagulation velocity at 0, 12, and 24 months was 5.49 [5.28 to 5.71] at 0 months, 5.53 [5.28 to 5.78] at 12 months, and 5.40 [5.13 to 5.68] at 24 months without anti-emicizumab antibody addition. On the other hand, 4.50 [4.36 to 4.64] at 0 months, 4.58 [4.41 to 4.75] at 12 months, and 4.39 [4.22 to 4.57] at 24 months for those with anti-emicizumab antibodies added. Relative to the Nara Medical University Hospital Institutional Reference Value (0%, 4.49; 100%, 7.51), the results were 33.3% [26.0% to 40.5%] for 0 months, 34.5% [26.1% to 42.8%] for 12 months, 30.2% [21.0% to 39.4%] for 24 months without anti-emicizumab antibody addition, 0% [-4.4% to 4.8%] at 0 months, 2.9% [-2.8% to 8.5%] at 12 months, and -3.2% [-9.0% to 2.6%] at 24 months with anti-emicizumab antibody added. 3. Evaluation of hemostasis status and occurrence of TMA or TE in clinical symptoms Hemostatic conditions were "effective" in 15 patients (83.3%, including 5 cases of hemorrhage due to rupture and 10 cases of surgery), "ineffective" in 0 patients (0.0%), "exacerbation" in 0 patients (0.0%), and "difficult to determine" in 3 patients (16.7%, including 2 events of hemorrhage due to rupture and 1 event of surgery). The incidence of TMA and TE was 0 in all patients. 4. Evaluation of general coagulation and hematological tests before and after bypass hemostatic agents administration, and that in regular samples The mean [95% CI] of each test value before administration of the bypass drug were as follows: Platelets: 27.38 [23.57 to 31.20]. FDP: 2.29 [0.28 to 4.31]. D-Dimer: 1.00[0.00 to 2.00]. PIC: 0.71[0.14 to 1.27] TAT: 3.21 [1.71 to 4.70]. The mean [95% CI] of each test value after administration of the bypass formulation were as follows: Platelets: 27.25 [23.16 to 31.34]. FDP: 2.47 [0.63 to 4.31]. D-Dimer: 0.92 [0.04 to 1.80]. PIC: 0.64[0.25 to 1.02] TAT: 5.43[3.18 to 7.68] The mean [95% CI] of each test value in periodic samples (0, 12, and 24 months) is as follows Platelets: 0 months: 26.32 [24.25 to 28.38]. 12 months: 25.50 [23.79 to 27.21]. 24 months: 25.41 [23.13 to 27.69] FDP: 0 month: 1.38 [1.11 to 1.64] 12 months: 1.55 [1.22 to 1.87] 24 months: 1.21 [0.97 to 1.46]. D-Dimer: 0 month: 0.28 [0.21 to 0.36] 12 months: 0.44[0.27 to 0.61] 24 months: 0.61 [0.49 to 0.73]. PIC: 0 month: 0.45[0.35 to 0.55] 12 months: 0.50[0.40 to 0.59] 24 months: 0.49 [0.36 to 0.62] TAT: 0 months: 1.91 [1.01 to 2.80] 12 months: 1.60 [1.30 to 1.91] 24 months: 1.17 [0.91 to 1.43]

In concomitant use of bypassing agent for breakthrough bleeding or surgical procedure of emicizumab-treated hemophilia A patients with inhibitor, recombinant activated factor 7 concentrate at dose of 90 or less micrograms/kg was effective and safe. The modified clot waveform analysis with optimized reagent for coagulation trigger was useful in these settings.

Mar. 31, 2024

Aug. 31, 2024

Yes

Data availability statements: The individual de-identified participant data will be shared upon reasonable request to the Contact for Scientific Queries. The data will become available from the end of the study until 5 years. Data sharing will be limited to requests from non-profit investigators and will be provided as electronic records.

https://jrct.niph.go.jp/latest-detail/jRCTs051190119

Nogami Keiji

Nara Medical University Hospital

840 Shijo-Cho, Kashihara, Nara,Japan

roc-noga@naramed-u.ac.jp

Ogiwara Kenichi

Nara Medical University Hospital

840 Shijo-Cho, Kashihara, Nara,Japan

+81-744-22-3051

ogiwarak@naramed-u.ac.jp

Complete

Mar. 06, 2020

Interventional

non-randomized controlled trial

open(masking not used)

active control

single assignment

treatment purpose

1. Congenital Hemophilia A with inhibitors over 4 years old
2. Patients treated or planned for emicizumab base on the latest package insert
3. Patients with written consent has been obtained, explaining the content of this clinical study
4. Patients who can comply with the planned procedure in this clinical study

1. Patients who have difficulty in regular visits and/or visits at the event
2. Patients with other diseases with abnormal liver function or platelets
3. Patients who have difficulty collecting blood
4. Judged by the investigator to be inappropriate for some reasons

Male

HemophiliaA with Inhibitor

Selection and administration dose of bypass hemostatic agents in rupture hemorrhage and hemostasis management during surgery

Degree of improvement in maximum coagulation rate by coagulation waveform analysis before and after administration of fixed-dose bypass hemostatic agents

1. Comparative evaluation with and without addition of anti-emicizumab antibody for changes of comprehensive coagulation parameter before and after administration of bypass hemostatic agents
2. Efficacy evaluation of emicizumab with and without addition of anti-emicizumab antibody using comprehensive coagulation tests in regular samples
3. Evaluation of hemostasis status and occurrence of TMA or TE in clinical symptoms
4. Evaluation of general coagulation and haematological tests before and after bypass hemostatic agents administration, and that in regular samples

+81-744-29-8835

Jan. 29, 2020

none