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The Effect of Riociguat for Peak Cardiac Index on Cardiopulmonary Exercise Test in Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Patients after Normalization of Pulmonary Artery Pressure by Combination Treatment of Riociguat and Balloon Pulmonary Angioplasty. (Riociguat-CTEPH)

THERAPY-HYBRID-BPA trial (THERAPY-HYBRID-BPA trial)

74

74 cases were enrolled as completed allocation. Of the cases, 73 (36 in the placebo group and 37 in the riociguat group) were adopted to the FAS and 71 (35 in the placebo group and 36 in the riociguat group) to the PPS. The mean and standard deviation (SD) of age in the FAS cases was 67.9 11.6 years, ranging from 34 to 84 years. 16 (21.9%) were male and 57 (78.1%) were female. The mean BMI was 23.0 (SD: 3.4) kg/m^2, and 60 cases (82.2%) fell under the class II and 13 cases (17.8%) to the class III in the WHO functional classification.There were no differences between groups.

Between November 25, 2020 and May 16, 2023, 18 of the 92 consenting cases were screened out and 74 were enrolled for allocation. 36 cases were assigned to the placebo group and 38 to the Riociguat group. Only 1 case in the Riociguat group was discontinued.

No adverse events (AE) leading to death were observed. Serious adverse events (SAE) included lumbar vertebral compression fracture (grade 2) in 1 case in the placebo group and vasovagal reaction (grade 3) and bipolar disorder (grade 3) in 1 case each in the riociguat group. All events were judged to be 'not related' to the study treatment and were confirmed to have completely recovered or mildly resolved. There were no discontinuations of study treatment due to AEs in either group. Ten cases (27.8%) in the placebo group and 14 cases (37.8%) in the riociguat group had any one of the adverse events defined as relatively high frequency for riociguat before the study. Events that occurred in 3 or more cases in either group were headache (3 (8.3%) in the placebo group and 2 (5.4%) in the riociguat group), edema of the extremities (2 (5.6%) in the placebo group and 5 (13.5%) in the riociguat group), hypotension (1 (2.8%) in the placebo group and 5 (13.5%) in the riociguat group), and hypertension (5 (13.9%) in the placebo group and 2 (5.4%) in the riociguat group). There was no statistically significant difference in the frequency of occurrence of any of these events in each group.

Outcome measures of efficacy: Primary endpoint: The mean change from baseline to follow-up in Peak CI (direct Fick test) was analyzed in the FAS population excluding cases in which Peak CI was missing at baseline or follow-up. The results were -1.41 L/min/m^2 (SD: 4.38) in the placebo group and -0.07 L/min/m^2 (SD: 2.35) in the riociguat group, with an adjusted difference of 1.09 L/min/m^2 (95% confidence interval: 0.20 to 1.97), which was statistically significant (p=0.017). AIPW estimation performed as a sensitivity analysis showed similar results (adjusted group difference: 1.02; 95% confidence interval: 0.19 to 1.96; p=0.011). Statistically significant differences were also observed when Peak CI was estimated by either thermodilution or indirect Fcik method. Furthermore, even when the population analyzed was the PPS, statistically significant differences were found in all tests as in the previous section. Secondary endpoints: The mean change from baseline in mPAP/CO slope (direct Fick method) at follow-up, calculated from resting and peak mPAP/CO slope, was 3.14 mmHg/L/min (SD: 7.40) in the placebo group and -3.28 mmHg/L/min (SD: 9.33) in the riosiguat group. The adjusted group difference was -5.80 mmHg/L/min (95% confidence interval: -9.52 to -2.07), a statistically significant difference (p=0.003). The mean change from baseline in mPAP/CO slope (direct Fick's method) at follow-up, calculated from 3 points: resting, 20 watts, and peak, was 1.61 mmHg/L/min (SD: 5.57) in the placebo group, -0.80 mmHg/L/min (SD: 5.28) in the riosiguat group, and -2.85 mmHg/L/min (95% CI: -5.49 to -0.21) in the riosiguat group. SD: 5.28), and the adjusted difference between groups was -2.85 mmHg/L/min (95% confidence interval: -5.49 to -0.21), which was statistically significant (p=0.035).

A study was conducted to compare the riociguat group with the placebo group in cases with CTEPH whose hemodynamics had normalized after BPA. Statistically significant differences were observed between the two groups, as well as no significant differences in safety. In conclusion, it was found that continuous administration of riociguat helped to further improve exercise tolerance and residual symptoms in cases with CTEPH.

June. 30, 2025

No

No plan

https://jrct.mhlw.go.jp/latest-detail/jRCTs041200052

Shimokawahara Hiroto

National Hospital Organization Okayama Medical Center

1711-1 Tamasu, Kita-ku, Okayama city, Okayama, 701-1192, Japan

nmc-admin@umin.ac.jp

Shimokawahara Hiroto

National Hospital Organization Okayama Medical Center

1711-1 Tamasu, Kita-ku, Okayama city, Okayama, 701-1192, Japan

+81-86-294-9911

nmc-admin@umin.ac.jp

Complete

Oct. 22, 2020

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

(1)Patients who meet CTEPH diagnostic criteria (complying with 2017 Japanese Cardiovascular Society Guidelines diagnostic criteria)
(2)Diagnosed as a contraindication of pulmonary endarterectomy by centraldiagnosis
(3)Patients who were adjusted to reach the appropriate dose of riociguat within 8weeks and were able to continueoral administration thereafter
(4)Patients who received BPA once or more after the dose adjustment of riociguat
(5)Patients who have been able to continue taking the same dose for more than 3months
(6)Patients who can obtain written informed consent from the patients and legal representatives
(7)Patients with WHO functional class II or III at the time of allocation
(8)Over the age of 18 and under 85 at the time of obtaining consent
(9)Patients with a resting CI value of less than 5.0 L/min/m2 in theright heart catheterization test immediatelybefore allocation
(10)Patients with a mean pulmonary artery pressure less than 25 mmHg in a rightheart catheterization test immediately before allocation

(1) Patients who are eligible for pulmonary endarterectomy (PEA)
(2) Patients With pulmonary hypertension other than class 4 by NICE classification
(3) Patients having difficulty in performing cardiopulmonary exercise test (CPET)
(4) Patients with severe right heart failure requiring cardiotonic drugs
(5) Patients with severe heart disease
(6) Patients with severe liver damage
(7) Patients with systolic blood pressure less than 90 mmHg at screening
(8) Patients with shunt disease
(9) (Contraindications) Patients with severe renal dysfunction (CCr <15 mL/min) or on dialysis
(10) Patients with life expectancy less than 2 years
(11) Being pregnant or lactating
(12) Patients who are contraindicated for riociguat
(13) Using other unlicensed drugs
(14) Patients who used a pulmonary vasodilator within 4 weeks after the consent of the right heart catheter test.
(15) Investigator determines that whose participation in this study is not appropriate

Both

chronic thromboembolic pulmonary hypertension

In this study, we will perform continuous verification by allocating the Chronic Thromboembolic Pulmonary Hypertension (CTEPH) patients whose hemodynamics were normalized after Balloon Pulmonary Angioplasty (BPA) to the the riociguat active group and placebo group for 16 weeks.

CTEPH

Double-Blind Placebo target

D000081029

D004311

Change in Peak CI during cardiopulmonary exercise test (CPET) from baseline to 16 weeks

1. Change in hemodynamic index during CPET from baseline to 16 weeks (Peak, 20W).
Cardiac output (CO), Pulmonary artery pressure (PAP), Pulmonary artery wedge pressure (PAWP), Right atrial pressure (RAP) Pulmonary vascular resistance (PVR), Total pulmonary resistance (TPR), Heart Rate (HR), Stroke volume (SV), Mixed venous oxygen saturation (SvO2), Percutaneous oxygen saturation (SpO2), Arterial oxygen saturation (SaO2), Arterial oxygen partial pressure (PaO2), PA compliance, Anaerobic threshold (AT), Mean PAP/CO slope, Peak VO2, Non-invasive blood pressure (NIBP), Arterial Blood Pressure (ABP), VE/VCO2, VE/VCO2 slope, End-tidal carbon dioxide partial pressure (PETCO2), Ratio of dead space to tidal volume (Vd/Vt)
2. Change in hemodynamic index at rest from baseline to 16 weeks.
(PAP, PAWP, CO, CI, RAP, PVR, TPR, HR, SV, SvO2, SpO2, PA compliance, NIBP)
3. Change in WHO functional classification from baseline to 16 weeks.
4. Change in 6-minute walking distance and modified Borg scale from baseline to 16 weeks.
5. Change in BNP value from baseline to 16 weeks.
6. Adverse events (AE)

+81-52-951-1111

Sept. 18, 2020

none