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

Study Overview
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Brief Summary
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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).

Official Title
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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

Conditions
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CTEPH

Intervention / Treatment
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* Drug: Edoxaban
* Drug: Warfarin Potassium
* Drug: Warfarin Potassium placebo
* Drug: Edoxaban placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Patients who are not planned to require increased / changed / discontinuation of PEA, BPA, or pulmonary vasodilators within 12months Stable administration of vitamin K antagonists WHO functional class I-III 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. Patients who have not undergone PEA from 180 days prior to baseline right heart catheterization to the start date of study drug administration Patients with a 6-minute walking distance >=150m Exclusion Criteria: Patients with severe lung disease (FEV1.0/FVC < 60% or %TLC < 60%) Patients with acute or chronic disabilities that interfere with clinical trial requirements Patients with acute symptomatic PE within 180 days prior to the start of study drug administration Patients with congenital heart disease who have not undergone radical surgery Patients who cannot provide informed consent due to mental disorders, dementia, or other illnesses Patients with advanced cancer Patients with a life expectancy of less than 1 year Patients with active hemorrhagic lesions Patients with comorbidities requiring vitamin K antagonist Patients receiving other study drug within 30 days prior to randomization Patients with renal dysfunction (Ccr 15 mL/min) Patients with liver dysfunction (Child-Pugh B or C) Females of reproductive age not using an acceptable form of contraception/Pregnant/Breastfeeding Patients contraindicated for edoxaban or warfarin Patients with hypersensitivity to any of the drug

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Edoxaban, DOAC, Wafrarin, Anticoagulation