臨床研究等提出・公開システム

An Investigator-initiated, multicenter, phase 3, randomized, single-blind, double-dummy, parallel-group study to evaluate the efficacy and safety of edoxaban versus warfarin (Vitamin K antagonist) in subjects with chronic thromboembolic pulmonaty hypertension taking warfarin (Vitamin K antagonist) at baseline (KABUKI)

Phase III Investigator-Initiated Trial to Investigate Safety and Efficacy of Edoxaban in Patients with Chronic Thromboembolic Pulmonary Hypertension (KABUKI)

74

Major demographic and other baseline characteristics were balanced between the treatment groups. The percentage of female subjects was 64.9% in the edoxaban group and 59.5% in the warfarin group, with a high proportion of female in both groups. The mean age was 61.7 years in the edoxaban group and 65.5 years in the warfarin group. The percentage of subjects with a history of pulmonary artery endarterectomy was 18.9% in the edoxaban group and 16.2% in the warfarin group. The percentage of subjects with a history of balloon pulmonary angioplasty was 100.0% in the edoxaban group and 94.6% in the warfarin group. The mean pulmonary vascular resistance (PVR) at rest was 2.413 Wood Units (WU) in the edoxaban group and 2.646 WU in the warfarin group.The mean 6-minute walk distance was 483.0 m in the edoxaban group and 481.3 m in the warfarin group.

Seventy-four subjects were enrolled (37 in the edoxaban group, 37 in the warfarin group), and all enrolled subjects received the study drug. Of the 74 patients, 4 patients discontinued the study drug (1 patient in the edoxaban group, 3 patients in the warfarin group), and 70 patients completed treatment with the study drug (36 patients in the edoxaban group, 34 patients in the warfarin group).

The incidence of clinically relevant bleeding was 2.7% (1/37) in the edoxaban group and 5.4% (2/37) in the warfarin group, with no difference between the two groups. The incidence of serious adverse events was 2.7% (1/37) in the edoxaban group and 8.1% (3/37) in the warfarin group. The serious adverse event in the edoxaban group was 1 case of pulmonary hypertension (not related to edoxaban), and the serious adverse events in the warfarin group were 1 case of transitional epithelial cancer (not related to warfarin), 1 case of bleeding stomach ulcer (related to warfarin), and 1 case of wisdom tooth extraction (not related to warfarin).

Primary outcome: In PPS analysis, the least squares mean (95%CI) of the ratio of log-transformed resting PVR at 1 year (visit 9) to log-transformed resting PVR at baseline was -0.069 (-0.149 - 0.010) for the edoxaban group and 0.014 (-0.068 - 0.096) for the warfarin group. The least squares mean difference between two groups (95%CI) was -0.083 (-0.198 - 0.031). The calculated upper limit of 0.031 for the two-sided 95% CI was below the non-inferiority margin of 0.172, demonstrating non-inferiority of the edoxaban group to the warfarin group. Secondary outcome: 1) Incidence of CTEPH worsening events No patients in either the edoxaban or warfarin groups experienced a CTEPH worsening event. 2) Changes in 6-minute walk distance The least-squares means of the change in 6-minute walk distance were 15.1 m for the edoxaban group and 9.0 m for the warfarin group at visit 5, 17.8 m for edoxaban and 9.7 m for warfarin at visit 7, and 18.7 m for edoxaban and 13.1 m for warfarin at visit 9. The least squares mean differences between two groups were 6.2 m at visit 5 (p = 0.6049), 8.1 m at visit 7 (p = 0.5053), and 5.6 m at visit 9 (p = 0.6120). None of the visits were significantly different, but the edoxaban group exceeded the warfarin group by 5.6 m at visit 9. 3) Change in NT-proBNP concentration The least-squares mean change in log-transformed NT-proBNP concentration was -0.034 in the edoxaban group and 0.020 in the warfarin group at visit 5, -0.026 in the edoxaban group and 0.151 in the warfarin group at visit 7, and -0.086 in the edoxaban group and 0.95 in the warfarin group at visit 9. The difference in least squares means between the two groups was -0.054 (p = 0.6510) at visit 5, -0.177 (p = 0.1012) at visit 7, and -0.181 (p = 0.0999) at visit 9.

The primary endpoint, the ratio of resting PVR at 1 year (Visit 9) to resting PVR at baseline, demonstrated the non-inferiority of the edoxaban group to the warfarin group. Secondary and exploratory endpoints did not differ between the edoxaban and warfarin groups. The incidence of clinically significant bleeding between the edoxaban and warfarin groups was similar, suggesting that edoxaban does not increase the risk of clinically significant bleeding compared with warfarin.

Aug. 01, 2024

Nov. 14, 2023

https://www.ahajournals.org/doi/epdf/10.1161/CIRCULATIONAHA.123.067528

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071200098

Abe Kohtaro

Kyushu University Hospital

3-1-1 Maidashi Higashi-ku Fukuoka 812-8582,Japan

abe.kotaro.232@m.kyushu-u.ac.jp

Hosokawa Kazuya

Kyushu University Hospital

3-1-1 Maidashi Higashi-ku Fukuoka 812-8582,Japan

+81-92-642-5360

hosokawa.kazuya.712@m.kyushu-u.ac.jp

Complete

Mar. 04, 2021

Interventional

randomized controlled trial

single blind

active control

parallel assignment

treatment purpose

1)Male and female patients >= 20 or =< 85 years of age
2)Patient who once* diagnosed with CTEPH based on imaging study (VQ scan, CT pulmonary angiogram) and hemodynamic criteria (MPAP >=25 mmHg and PAWP =< 15 mmHg). *Patients treated with PEA, BPA, or vasodilators, who do not meet hemodynamic criteria at the registration, are eligible.
3)Patients who are not planned to require increased / changed / discontinuation of PEA, BPA, or pulmonary vasodilators within 12 months
4)Stable administration of vitamin K antagonists
5)WHO functional class I-III
6)Patients who meet A) B) and C) by 90 days prior to baseline
A)No addition, reduction, or change of endothelin antagonists, soluble guanylate cyclase stimulants, phosphodiesterase-5 inhibitors, prostacyclin and its derivatives, prostacyclin agonist, or calcium antagonists
B)Appropriate anticoagulants have been continued
C)No BPA has been done
7)Patients who have not undergone PEA from 180 days prior to baseline right heart catheterization to the start date of study drug administration
8)Patients with a 6-minute walking distance >=150m

1)Patients with severe lung disease (FEV1.0/FVC < 60% or %TLC < 60%)
2)Patients with acute or chronic disabilities that interfere with clinical trial requirements
3)Patients with acute symptomatic PE within 180 days prior to the start of study drug administration
4)Patients with congenital heart disease who have not undergone radical surgery
5)Patients who cannot provide informed consent due to mental disorders, dementia, or other illnesses
6)Patients with advanced cancer
7)Patients with a life expectancy of less than 1 year
8)Patients with active hemorrhagic lesions
9)Patients with comorbidities requiring vitamin K antagonist
10)Patients receiving other study drug within 30 days prior to randomization
11)Patients with renal dysfunction (Ccr <15 mL/min)
12)Patients with liver dysfunction (Child-Pugh B or C)
13)Females of reproductive age not using an acceptable form of contraception/Pregnant/Breastfeeding
14)Patients contraindicated for edoxaban or warfarin
15)Patients with hypersensitivity to any of the drug additives
16)Patients judged unsuitable by investigators

Both

Chronic Thromboembolic Pulmonary Hypertension

Oral administeration of (1) or (2)
(1) Edoxaban group
- Edoxaban 30 mg/60 mg tablet according to body weight.
60 kg or less: 30 mg once daily
over 60 kg: 60 mg once daily
(reduced to 30 mg once daily depending on renal function and concomitant medications)

- Warfarin K 1 mg placebo tablets once daily

(2)Warfarin group
- Edoxaban 30 mg/60 mg placebo tablet according to body weight.
60 kg or less: 30 mg once daily
over 60 kg: 60 mg once daily
(reduced to 30 mg once daily depending on renal function and concomitant medications)

- Warfarin K 1 mg tablets once daily (Dose adjusted with target PT-INR of 1.5-2.5)

CTEPH, DOAC, warfarin

Oral administeration

D000284

Ratio of 1-year resting PVR to baseline resting PVR

Efficacy
1)Percentage of cases with CTEPH exacerbation events
2)Change from baseline in distance of 6-minute walking test (Visit 5, 7, 9)
3)Change from baseline in WHO functional classification class (Visit 5, 7, 9)
4)Change from baseline in NT-proBNP concentration (Visit 5, 7, 9)

Safety
Percentage of cases with clinically significant bleeding

+81-92-642-5774

Aug. 31, 2020

none