臨床研究等提出・公開システム

A PK/PD study of oral FXa inhibitor Edoxaban Tosilate Hydrate in patients with nonvalvular atrial fibrillation (NVAF) who have developed acute heart failure.

none

26

The study subject characteristics of the 26 subjects included in the safety-analysis set were as follows: There were 18 men (69.2%) and 8 women (30.8%). They were aged 71 +/- 11 years (mean +/- standard deviation), weighing 64.9 +/- 20.2 kg (mean +/- standard deviation), with a BMI of 24.3 +/- 4.4 kg/m2 (mean +/- standard deviation) and a CLCR level of 64.2 +/- 66.9 mL/min (mean +/- standard deviation). Atrial fibrillation (AF) was classified as paroxysmal AF in 9 subjects (34.6%), persistent AF in 10 subjects (38.5%), long-term persistent AF in 6 subjects (23.1%), and permanent AF in 1 subject (3.8%). The CHADS2 score was 0 or 1 in 6 subjects (23.1%), 2 in 9 subjects (34.6%), and 3 or greater in 11 subjects (42.3%). Blood pressure and heart rate prior to or at enrollment were as follows: systolic blood pressure, 125 +/- 28 mmHg (mean +/- standard deviation); diastolic blood pressure, 87 +/- 21 mmHg (mean +/- standard deviation); and heart rate, 120 +/- 33 beats/min (mean +/- standard deviation). Heart failure was classified on the basis of left ventricular ejection fraction (LVEF) as HFrEF in 16 subjects (61.5%), HFmrEF in 6 subjects (23.1%), and HFpEF in 4 subjects (15.4%). The following complications were reported in 5 or more subjects: hypertension in 14 subjects (53.8%), dyslipidemia in 7 subjects (26.9%), diabetes mellitus (including diabetic complications) in 7 subjects (26.9%), renal disease in 17 subjects (65.4%), tachycardiac atrial fibrillation (except arrythmia) in 7 subjects (26.9%), hepatic dysfunction in 10 subjects (38.5%), chronic respiratory disease in 7 subjects (26.9%), hyperuricemia in 13 subjects (50.0%), and other complications in 10% (38.5%). Pre-admission treatment with edoxaban was absent in 13 subjects (50.0%) and present in 13 subjects (50.0%). The dosing regimen on Day 1 was 30 mg once daily in 21 (80.8%) of the 26 subjects and 60 mg once daily in the remaining 5 subjects (19.2%). One of the 21 subjects who received 30 mg once daily on Day 1 had the dosage changed to 60 mg once daily for only 2 days but subsequently continued treatment on the original 30 mg once daily regimen. No dosage change occurred in any other subjects. The median observation period was 10 (range: 7 - 46) days, with a mean of 13 +/- 8 days (mean +/- standard deviation).

Twenty-six subjects were enrolled in this study (none of whom provided consent for additional blood sampling). All the 26 subjects enrolled in this study were administrated the study drug as specified in the protocol. All of them completed the study without discontinuations. All the 26 subjects enrolled in this study were included in the safety-analysis set and the analysis population for routine testing. Since consent for additional testing was not obtained from any of the 26 subjects enrolled in this study, no additional blood sampling was performed, resulting in no subjects being included in the analysis population for additional testing.

During the observation period, none of the following events occurred: death (including death due to cardiovascular disease), stroke (excluding TIA), systemic embolism, ischemic stroke, hemorrhagic stroke, major bleeding, and intracranial hemorrhage. In addition, there were no serious adverse events (including death), serious side effects, or adverse events leading to discontinuation. Overall, adverse events were observed in 12 subjects during the study. During the observation period, adverse events were observed in 11 subjects (42.3%). The number of subjects who experienced adverse events by dosing regimen on Day 1 was 8 (38.1%) of the 30 mg once daily regimen and 3 (60.0%) of the 60 mg once daily regimen. Outside the observation period (between informed consent and Day 1), one subject experienced an adverse event. One of these events (1 subject, 3.8%) was considered to be a side effect for which a causal relationship to the study drug was not ruled out. The following adverse events were observed during the observation period: insomnia, erythema, renal impairment, and post procedural haematuria in 2 subjects each (7.7%); and device related infection, hyperuricaemia, decreased appetite, delirium, vagus nerve disorder, hypotension, abdominal discomfort, constipation, nausea, mucosal prolapse syndrome, seborrhoeic dermatitis, gynaecomastia, protein induced by vitamin K absence or antagonist II increased, lip injury, and procedural pain in 1 subject each (3.8%). Outside the observation period, insomnia was observed in 1 subject. The following adverse event was considered to be a side effect: protein induced by vitamin K absence or antagonist II increased, which was observed in 1 subject (3.8%). All of these adverse events were non-serious. The outcome of the adverse events observed during the observation period was "not recovered/not resolved" for protein induced by vitamin K absence or antagonist II increased; "recovering/resolving" for erythema, renal impairment and post procedural haematuria, which were observed in 2 subjects each, and hyperuricaemia, delirium, hypotension, constipation, mucosal prolapse syndrome, seborrhoeic dermatitis, gynaecomastia, lip injury and procedural pain, which were observed in 1 subject each; and "recovered/resolved" for the other events. The insomnia observed in 1 subject outside the observation period was found to be "recovering/resolving." Laboratory test results showed no abnormal changes in hematology or blood chemistry parameters except an adverse event of protein induced by vitamin K absence or antagonist II increased, which occurred in a subject who received 60 mg once daily.

Time courses of trough plasma edoxaban concentration and ratios of trough plasma edoxaban concentration on Days 1-7 to that on the last sampling day: primary endpoints - Time courses of trough plasma edoxaban concentration The trough plasma edoxaban concentration (mean +/- standard deviation) of the 26 subjects included in the analysis population for routine testing (25 subjects on Days 3 and 6 [due to delayed dosing in SubjectID 5-02 and 1-02]) were 32.5 +/- 24.7 ng/mL on Day 1, 30.2 +/- 15.9 ng/mL on Day 2, 28.4 +/- 15.0 ng/mL on Day 3, 28.3 +/- 13.2 ng/mL on Day 4, 27.1 +/- 14.3 ng/mL on Day 5, 27.6 +/- 13.1 ng/mL on Day 6, 27.7 +/- 15.0 ng/mL on Day 7, and 29.1 +/- 12.7 ng/mL on the last sampling day. The trough plasma edoxaban concentration (mean +/- standard deviation) of the 30 mg once daily regimen in the analysis population for routine testing were 28.3 +/- 20.1 ng/mL on Day 1, 32.3 +/- 16.8 ng/mL on Day 2, 30.1 +/- 15.6 ng/mL on Day 3, 30.0 +/- 13.1 ng/mL on Day 4, 29.0 +/- 15.1 ng/mL on Day 5, 29.2 +/- 13.9 ng/mL on Day 6, 30.0 +/- 15.6 ng/mL on Day 7, and 30.8 +/- 13.5 ng/mL on the last sampling day. The trough plasma edoxaban concentration (mean +/- standard deviation) of the 60 mg once daily regimen were 50.4 +/- 35.8 ng/mL on Day 1, 21.5 +/- 7.0 ng/mL on Day 2, 19.4 +/- 7.3 ng/mL on Day 3, 21.0 +/- 12.2 ng/mL on Day 4, 18.9 +/- 5.7 ng/mL on Day 5, 20.8 +/- 6.9 ng/mL on Day 6, 17.9 +/- 6.8 ng/mL on Day 7, and 22.1 +/- 4.6 ng/mL on the last sampling day. The summary statistics of trough plasma edoxaban concentration (mean +/- standard deviation) stratified by pre-admission treatment status with edoxaban in the analysis population for routine testing were 46.1 +/- 24.7 ng/mL on Day 1, 29.5 +/- 12.6 ng/mL on Day 2, 29.6 +/- 13.2 ng/mL on Day 3, 29.7 +/- 13.8 ng/mL on Day 4, 27.0 +/- 14.0 ng/mL on Day 5, 27.2 +/- 11.9 ng/mL on Day 6, 27.4 +/- 15.6 ng/mL on Day 7, and 29.7 +/- 12.6 ng/mL on the last sampling day in the subjects who had not received edoxaban before admission, and 18.9 +/- 16.0 ng/mL on Day 1, 30.9 +/- 19.2 ng/mL on Day 2, 27.3 +/- 16.9 ng/mL on Day 3, 26.9 +/- 12.9 ng/mL on Day 4, 27.2 +/- 15.1 ng/mL on Day 5, 28.0 +/- 14.8 ng/mL on Day 6, 27.9 +/- 15.1 ng/mL on Day 7, and 28.6 +/- 13.3 ng/mL on the last sampling day in those who had received edoxaban before admission. - Time courses of ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day The ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day (mean +/- standard deviation) for the 26 subjects included in the analysis population for routine testing (25 subjects on Days 3 and 6 [due to delayed dosing in Subject ID 5-02 and 1-02]) were 1.254 +/- 1.170 on Day 1, 1.070 +/- 0.407 on Day 2, 1.012 +/- 0.410 on Day 3, 1.038 +/- 0.406 on Day 4, 0.959 +/- 0.336 on Day 5, 1.015 +/- 0.310 on Day 6, and 0.948 +/- 0.255 on Day 7. The ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day (mean +/- standard deviation) of the 30 mg once daily regimen in the analysis population for routine testing were 0.954 +/- 0.681 on Day 1, 1.079 +/- 0.411 on Day 2, 1.031 +/- 0.414 on Day 3, 1.043 +/- 0.350 on Day 4, 0.976 +/- 0.342 on Day 5, 1.023 +/- 0.292 on Day 6, and 0.969 +/- 0.218 on Day 7.The ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day (mean +/- standard deviation) of the 60 mg once daily regimen were 2.515 +/- 1.943 on Day 1, 1.032 +/- 0.432 on Day 2, 0.913 +/- 0.435 on Day 3, 1.021 +/- 0.645 on Day 4, 0.890 +/- 0.336 on Day 5, 0.987 +/- 0.416 on Day 6, and 0.862 +/- 0.396 on Day 7. Estimated ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day based on a liner mixed-effects model The geometric least-squares mean ratios of plasma edoxaban concentration on Days 1-7 to that on the last sampling day and corresponding 90% confidence intervals (shown in parentheses) were 0.933 (0.665 to 1.309) on Day 1, 0.987 (0.856 to 1.138) on Day 2, 0.925 (0.803 to 1.066) on Day 3, 0.955 (0.824 to 1.107) on Day 4, 0.905 (0.805 to 1.018) on Day 5, 0.947 (0.847 to 1.059) on Day 6, and 0.911 (0.822 to 1.009) on Day 7. Pharmacokinetics: Pharmacokinetic parameters of plasma edoxaban concentration on Day 1 and the last sampling day (Cmax, AUCtau, and Tmax): secondary endpoints The pharmacokinetic parameters (Cmax, AUCtau, and Tmax) were not calculated because no subjects gave consent for additional blood sampling. Pharmacodynamic (PD) evaluation: secondary endpoints F1+2 levels (mean +/- standard deviation) of the 26 subjects included in the analysis population for routine testing (25 subjects on Days 3 and 6 [due to delayed dosing in Subject ID 5-02 and 1-02]) were 170 +/- 87 pmol/L on Day 1, 169 +/- 85 pmol/L on Day 2, 162 +/- 78 pmol/L on Day 3, 170 +/- 101 pmol/L on Day 4, 170 +/- 98 pmol/L on Day 5, 162 +/- 102 pmol/L on Day 6, 170 +/- 126 pmol/L on Day 7, and 167 +/- 128 pmol/L on the last sampling day. The changes in F1+2 (F1+2 level at each assessment time minus that on the last sampling day) were 3 +/- 121 pmol/L on Day 1, 3 +/- 94 pmol/L on Day 2, -4 +/- 91 pmol/L on Day 3, 3 +/- 72 pmol/L on Day 4, 3 +/- 61 pmol/L on Day 5, -5 +/- 51 pmol/L on Day 6, and 3 +/- 34 pmol/L on Day 7. D-dimer levels (mean +/- standard deviation) were 1.52 +/- 1.34 micrograms/mL on Day 1, 1.55 +/- 1.77 micrograms/mL on Day 2, 1.56 +/- 2.03 micrograms/mL on Day 3, 1.68 +/- 2.68 micrograms/mL on Day 4, 1.69 +/- 3.01 micrograms/mL on Day 5, 1.56 +/- 2.59 micrograms/mL on Day 6, 1.46 +/- 2.39 micrograms/mL on Day 7, and 0.81 +/- 1.00 micrograms/mL on the last sampling day. The changes in D-dimer (D-dimer level at each assessment time minus that on the last sampling day) were 0.72 +/- 1.11 micrograms/mL on Day 1, 0.74 +/- 1.27 micrograms/mL on Day 2, 0.74 +/- 1.61 micrograms/mL on Day 3, 0.87 +/- 2.14 micrograms/mL on Day 4, 0.88 +/- 2.66 micrograms/mL on Day 5, 0.75 +/- 2.23 micrograms/mL on Day 6, and 0.66 +/- 1.87 micrograms/mL on Day 7. PT was not measured because no subjects gave consent for additional blood sampling.

This study provided the first evidence that the plasma concentration and PD of edoxaban were constant at steady-state during hospitalization in patients with NVAF and acute heart failure. The plasma concentration and PD profiles of edoxaban observed in this study were generally consistent with the previous data from studies involving NVAF patients without acute heart failure. These results provide valuable information to use edoxaban safely in patients with NVAF who have developed acute heart failure.

April. 02, 2021

Mar. 30, 2021

https://link.springer.com/article/10.1007%2Fs40262-021-00999-y

No

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs031190006

Nabeta Takeru

Kitasato University Hospital

1-15-1 Minamikukitasato, Sagamihara-shi, Kanagawa-ken, 252-0373 Japan

nabetake@med.kitasato-u.ac.jp

Nabeta Takeru

Kitasato University Hospital

1-15-1 Minamikukitasato, Sagamihara-shi, Kanagawa-ken, 252-0373 Japan

+81-42-778-8111

nabetake@med.kitasato-u.ac.jp

Complete

Feb. 01, 2019

Interventional

non-randomized controlled trial

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1. Patients who required hospitalization due to acute heart failure (including acute exacerbation of chronic heart failure)
2. Patients who received a definitive diagnosis of NVAF
3. Patients who are administered Edoxaban Tosilate Hydrate on obtaining informed consent or patients who will newly start administration of Edoxaban Tosilate Hydrate after obtaining informed consent
4. Patients who is available for oral administration at registration
5. Aged 20 years or older on obtaining informed consent

1. Patients using oral anticoagulant other than Edoxaban Tosilate Hydrate at the time of admission
2. Patients with a past medical history of hypersensitivity to Edoxaban Tosilate Hydrate
3. Patients with acute bacterial endocarditis
4. Patients with renal failure (creatinine clearance calculated by Cockcroft-Gault equation is less than 15 mL/min)
5. Patients who is receiving Dual anti-platelet therapy (DAPT)
6. Patients with cardiopulmonary arrest or cardiogenic shock
7. Patients who had gastrointestinal bleeding or major bleeding (ISTH criteria) within 4 weeks of enrollment
8. Patients who are unlikely to complete research, such as progressive malignant tumor merger
9. Pregnant patients
10. Patients who have been enrolled in this study in the past
11. Participating or scheduled to participate in clinical studies with intervention
12. Patients who have been judged inappropriate as the subjects of this study by the principle investigator and others

Both

Nonvalvular atrial fibrillation which has developed acute cardiac heart failure

Treatment with Edoxaban Tosilate Hydrate will be selected as antithrombotic treatment.

acute cardiac insufficiency, nonvalvular atrial fibrillation

1. Ratio of trough value at the administration from day 1 to 7 to the concentration of Edoxaban plasma (trough value) at the time of final blood drawing
2. Transition of Edoxaban Tosilate Hydrate plasma concentration (trough value) (from day 1 to the final blood drawing)

1. Pharmacokinetics
Pharmacokinetic parameters (Cmax, AUCtau, Tmax) of plasma Edoxaban Tosilate Hydrate on day 0 of administration and at the last blood drawing
2. Pharmacodynamics
Changes in the following pharmacodynamic biomarkers at the blood drawing
1) Prothrombin fragment 1 + 2 (Fl + 2)
2) D-dimer
3) PT

+81-42-778-8273

Feb. 14, 2019

none