Clinical Trial to Investigate Safety and Efficacy of Edoxaban in Patients With CTEPH (KABUKI)

An Investigator-initiated, Multicenter, Phase 3, Randomized, Single-blind, Double-dummy, Parallel-group Study of Evaluate the Efficacy and Safety of Edoxaban Versus Warfarin (Vitamin K Antagonist) in Subjects With Chronic Thromboembolic Pulmonary Hypertension Taking Warfarin (Vitamin K Antagonist) at Baseline: KABUKI

This is phase III trial to evaluate whether edoxaban, a direct factor Xa inhibitor, is noninferior to warfarin in preventing worsening of chronic thromboembolic pulmonary hypertension (CTEPH).

Study Overview

• Status: Completed
• Conditions: CTEPH
• Intervention / Treatment: Drug: Edoxaban; Drug: Warfarin Potassium placebo; Drug: Warfarin Potassium; Drug: Edoxaban placebo

• Study Type: Interventional
• Enrollment (Actual): 74
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Fukuoka, Japan, 812-8582
    • Kyushu University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patient who once* diagnosed with CTEPH based on at least 2 imaging study (VQ scan, CT pulmonary angiogram, or catheter-based 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.
2. Patients who are not planned to require increased / changed / discontinuation of PEA, BPA, or pulmonary vasodilators within 12months
3. Stable administration of vitamin K antagonists
4. WHO functional class I-III
5. 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, or calcium antagonists. B)Appropriate anticoagulants have been continued. C)No BPA has been done.
6. Patients who have not undergone PEA from 180 days prior to baseline right heart catheterization to the start date of study drug administration
7. Patients with a 6-minute walking distance >=150m

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Edoxaban group	Drug: Edoxaban; - 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; Drug: Warfarin Potassium placebo; - Warfarin K 1 mg placebo tablets once daily
Active Comparator: Warfarin group	Drug: Warfarin Potassium; - Warfarin K 1 mg tablets once daily (Dose adjusted with target PT-INR of 1.5-2.5); Drug: Edoxaban placebo; - 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Ratio of 1-year resting PVR to baseline resting PVR	Week 48 of treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Percentage of cases with worsening of CTEPH	Throughout the study duration(up to week48)
Change from baseline in 6-minute walk distance	Week16, 32, 48 of treatment
Change from baseline in WHO functional class	Week16, 32, 48 of treatment
Change from baseline in NT-proBNP	Week16, 32, 48 of treatment
Percentage of cases with clinically relavant bleeding (ISTH 2015 definition)	Throughout the study duration(up to week48)

Collaborators and Investigators

• Sponsor: Kyushu University
• Collaborators: Daiichi Sankyo Co., Ltd.
• Investigators: Principal Investigator: Kohtaro Abe, Kyushu University Hospital

Publications and helpful links

General Publications

• Hosokawa K, Abe K, Tsutsui H. Use of direct oral anticoagulants prevents increase in pulmonary vascular resistance and incidence of clinical worsening in patients with chronic thromboembolic pulmonary hypertension. Thromb Res. 2019 Aug;180:43-46. doi: 10.1016/j.thromres.2019.05.018. Epub 2019 May 31. No abstract available.

Study record dates

Study Major Dates

• Study Start (Actual): March 23, 2021
• Primary Completion (Actual): March 30, 2023
• Study Completion (Actual): June 27, 2023

Study Registration Dates

• First Submitted: January 25, 2021
• First Submitted That Met QC Criteria: January 25, 2021
• First Posted (Actual): January 29, 2021

Study Record Updates

• Last Update Posted (Actual): October 5, 2023
• Last Update Submitted That Met QC Criteria: October 3, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Anticoagulation; Edoxaban; DOAC; Wafrarin
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Edoxaban; Warfarin
• Other Study ID Numbers: CTR225-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Data are available upon reasonable request. The deidentified participant data collected in this study will be shared with manufacturers of investigational drugs, Ministry of Health, Labor and Welfare, and regulatory authorities related to pharmaceutical affairs.

Data are attributed to Kyushu University and Daiichi Sankyo Co., Ltd. Protocols, informed consent form, and statistical analysis plans will be shared upon reasonable request.

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

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No