Efficacy and safety of edoxaban in patients with chronic thromboembolic pulmonary hypertension: protocol for a multicentre, randomised, warfarin-controlled, parallel group trial - KABUKI trial

Figures

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  Figure 1. Pathogenesis of CTEPH and potential targets of action of edoxaban. Large pulmonary thromboembolism and/or small recurrent asymptomatic pulmonary thromboembolism may cause the development of CTEPH. Incomplete clot dissolution causes persistent pulmonary circulation impairment and consequently leads to pulmonary hypertension. Turbulent and slow blood flow promotes clot formation at the organised thrombotic lesions and distal vessels (in situ thrombosis). In open vessels, excessive blood flow and compensatory blood flow impair small vessels. The KABUKI trial seeks to verify whether edoxaban prevents recurrent PE, incomplete clot dissolution and in situ thrombosis. CTEPH, chronic thromboembolic pulmonary hypertension; PE, pulmonary thromboembolism.

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  Figure 2. Study flow diagram. After obtaining consent, the subjects undergo eligibility screening and right heart catheterisation including pulmonary vascular resistance measurement. Subjects will be randomly assigned to the edoxaban group or the warfarin group at 1:1 ratio. The investigators will carry out a 1 year observation that includes monthly or bimonthly visits. At the final visit, the subjects will again undergo right heart catheterisation to measure pulmonary vascular resistance.

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  Figure 3. Study time course. After screening for eligibility, warfarin used at baseline is switched to warfarin placebo (dummy, edoxaban group) or unlabeled warfarin (warfarin group) in the period of switching to test drug. At the commencement of intervention, the edoxaban group starts edoxaban while continuing warfarin placebo after confirming prothrombin time-international normalised ratio below the therapeutic level, and the warfarin group continues warfarin with additional edoxaban placebo, in a double-dummy fashion. The black and red ellipses indicate warfarin (or warfarin placebo) tablet and edoxaban (or edoxaban placebo) tablet, respectively. After 1 year observation, the subjects will undergo right heart catheterisation. CTEPH, chronic thromboembolic pulmonary hypertension; WHO-FC, WHO functional class.

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  Figure 4. Projected study timeline. Approximate KABUKI trial timeline is shown from enrolment of the first patient. Key study benchmarks are shown. The study ends when 74 subjects complete the evaluation or drop out from the trial. The estimated recruitment period is 1 year, and the observation period is 1 year.