Effect of riociguat on exercise following balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension in Japan (THERAPY-HYBRID-BPA): a multicentre, double-blind, randomised, controlled, phase 4 trial.

This study aimed to evaluate the efficacy during an exercise test and the safety of the continuation of riociguat post-BPA in patients with inoperable CTEPH and normalised haemodynamic variables.

本研究旨在评估不可手术的CTEPH患者在BPA后继续使用利奥西呱进行运动测试的疗效和安全性，这些患者的血流动力学变量已恢复正常。

Methods

This multicentre, double-blind, randomised, controlled, phase 4 trial was conducted at four high-volume CTEPH centres in Japan.

这项多中心、双盲、随机、对照的4期临床试验在日本四个高容量CTEPH中心进行。

Patients aged 18-85 years with a confirmed diagnosis of inoperable, WHO functional class II-IV CTEPH, and a resting mean pulmonary arterial pressure (mPAP) of 25 mm Hg or higher and pulmonary vascular resistance of 3·0 Wood units or higher on right-heart catheterisation, received riociguat and BPA at screening.

年龄在18至85岁之间，确诊为无法手术的WHO功能II-IV级CTEPH患者，且在右心导管检查中静息平均肺动脉压（mPAP）≥25 mm Hg和肺血管阻力≥3·0 Wood单位，这些患者在筛选时接受了利奥西呱和BPA治疗。

Screened patients with a resting cardiac index of less than 5·0 L/min per m2 and mPAP of less than 25 mm Hg 3 months after the final BPA procedure were randomly assigned (1:1) either to receive placebo three times daily for 16 weeks or to continue taking riociguat three times daily for 16 weeks at a dose established during the screening period, which varied per patient from 1·0 mg to 2·5 mg.

在最后一次球囊肺动脉成形术（BPA）后3个月，筛选出静息心指数小于5.0 L/min/m2且平均肺动脉压（mPAP）小于25 mm Hg的患者，按1:1的比例随机分配，要么每天三次接受安慰剂治疗16周，要么继续每天三次服用在筛选期间确定剂量的利奥西呱治疗16周，剂量根据患者情况从1.0 mg到2.5 mg不等。

Randomisation was done via an online system with a block size of 8 based on the allocation factors of medical institution and riociguat dose at allocation; patients and investigators were masked to treatment assignment.

随机分组通过一个基于医疗机构和分配时利奥西呱剂量的分配因素，采用块大小为8的在线系统进行；患者和研究人员对治疗分配情况不知情。

The primary endpoint was the change in peak cardiac index calculated using the direct Fick method during a cardiopulmonary exercise test (CPET) from baseline to week 16, and was measured in the full analysis set (ie, all randomly assigned patients apart from those who had withdrawn consent, had severe protocol violations, or had never taken the active drug or placebo) in all patients with available data.

主要终点是使用直接Fick法在心肺运动测试（CPET）中从基线到第16周心脏指数峰值的变化，并在所有有可用数据的患者中进行测量，即在全分析集（即所有随机分配的患者，除了那些已撤回同意、有严重协议违规或从未服用过活性药物或安慰剂的患者）中进行测量。

The safety analysis included all patients who had taken at least one dose of the active drug or placebo.

安全性分析包括所有至少服用过一次活性药物或安慰剂的患者。

The trial was registered with the Japan Registry of Clinical Trials (jRCTs041200052) and ClinicalTrials.gov (NCT04600492) and is now closed.

该试验已在日本临床试验注册中心(jRCTs041200052)和ClinicalTrials.gov(NCT04600492)注册，并已关闭。

Results

Between Nov 25, 2020, and May 16, 2023, 74 patients (including 58 female patients and 16 male patients) were enrolled and randomly assigned, 36 to the riociguat-discontinuing group and 38 to the riociguat-continuing group. 32 patients in the riociguat-discontinuing group and 34 in the riociguat-continuing group were included in the primary analysis after exclusion of patients with missing data.

在2020年11月25日至2023年5月16日期间，共有74名患者（包括58名女性患者和16名男性患者）被纳入研究并随机分配，其中36名患者分配到停止利奥西呱组，38名患者分配到继续利奥西呱组。在排除了数据缺失的患者后，共有32名患者在停止利奥西呱组和34名患者在继续利奥西呱组被纳入主要分析。

The adjusted mean of peak cardiac index during CPET changed from baseline to week 16 by -1·11 L/min per m2 (95% CI -2·14 to -0·09) in the riociguat-discontinuing group and by -0·03 L/min per m2 (-1·04 to 0·99) in the riociguat-continuing group (intergroup difference 1·09 L/min per m2 [95% CI 0·20-1·97]; p=0·017).

在CPET期间，与基线相比，停用利奥西呱组的峰值心脏指数调整平均值在第16周时变化为-1.11 L/min/m2（95% 置信区间 -2.14至-0.09），而继续使用利奥西呱组的变化为-0.03 L/min/m2（95% 置信区间 -1.04至0.99）（组间差异为1.09 L/min/m2 [95% 置信区间 0.20-1.97]；p=0.017）。

Non-serious adverse events occurred in ten (28%) patients in the riociguat-discontinuing group and 14 (38%) patients in the riociguat-continuing group (p=0·36).

在停用利奥西呱组有10名（28%）患者出现非严重不良事件，在继续使用利奥西呱组有14名（38%）患者出现非严重不良事件（p=0.36）。

No deaths were observed.

未观察到死亡事件。

interpretation

Our findings suggested that the continuation of riociguat post-BPA might attenuate the worsening of exercise intolerance without increasing the risk of adverse events; discontinuation might require more careful consideration.

我们的研究结果表明，肺动脉球囊扩张术后继续使用利奥西呱可能会减缓运动耐受性恶化，而不会增加不良事件的风险；停药可能需要更慎重的考虑。

These results should be explored in long-term studies.

这些结果应在长期研究中进一步探索。

funding

Bayer Yakuhin, Bayer, and Merck Sharp & Dohme.

拜耳医药、拜耳以及默克夏普与多姆公司。