A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH.

Pulmonary Hypertension Clinical Trial

— CHEST-1  

Official title:

Randomized, Double-blind, Placebo-controlled, Multi-centre, Multi-national Study to Evaluate the Efficacy and Safety of Oral BAY63-2521 (1 mg, 1.5 mg, 2 mg, or 2.5 mg Tid) in Patients With Chronic Thromboembolic Pulmonary Hypertension (CTEPH)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00855465
• Other study ID #: 11348
• Secondary ID: 2007-000072-16
• Status: Completed
• Phase: Phase 3
• Start date: February 23, 2009
• Est. completion date: June 27, 2012

Study information

• Verified date: November 2023
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The aim of the study is to assess the efficacy and safety of different doses of BAY63-2521, given orally for 16 weeks, in patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH).

Description:

Adverse event data will be covered in Adverse events section.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 262
• Est. completion date: June 27, 2012
• Est. primary completion date: June 27, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

Inclusion Criteria:

• Male and female patients with CTEPH either inoperable or with persistent or recurrent PH after surgery.

Exclusion Criteria:

• All types of pulmonary hypertension except subtypes 4.1 and 4.2 of the Venice Clinical Classification of Pulmonary Hypertension.

Related Conditions & MeSH terms

• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension

Intervention

Drug:
• Riociguat (Adempas, BAY63-2521)
BAY63-2521: 1 mg tid - 2,5 mg tid orally for 16 weeks.
• Placebo
Matching Placebo tid orally for 16 weeks

Locations

Country	Name	City	State
Czechia	Vseobecna fakultni nemocnice	Praha 2
France	Hopital Antoine Beclere	Clamart Cedex

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Belgium,  Brazil,  Canada,  China,  Czechia,  Denmark,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Mexico,  Netherlands,  Poland,  Portugal,  Russian Federation,  Slovakia,  Spain,  Switzerland,  Taiwan,  Turkey,  United Kingdom, 

References & Publications (9)

Archer SL. Riociguat for pulmonary hypertension--a glass half full. N Engl J Med. 2013 Jul 25;369(4):386-8. doi: 10.1056/NEJMe1306684. No abstract available. — View Citation

Benza RL, Boucly A, Farber HW, Frost AE, Ghofrani HA, Hoeper MM, Lambelet M, Rahner C, Bansilal S, Nikkho S, Meier C, Sitbon O. Change in REVEAL Lite 2 risk score predicts outcomes in patients with pulmonary arterial hypertension in the PATENT study. J He — View Citation

Benza RL, Farber HW, Frost AE, Ghofrani HA, Corris PA, Lambelet M, Nikkho S, Meier C, Hoeper MM. Application of the REVEAL risk score calculator 2.0 in the CHEST study. Respir Med. 2022 Apr-May;195:106783. doi: 10.1016/j.rmed.2022.106783. Epub 2022 Mar 1. — View Citation

Ghofrani HA, D'Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G, Wang C; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. — View Citation

Ghofrani HA, Humbert M, Langleben D, Schermuly R, Stasch JP, Wilkins MR, Klinger JR. Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension. Chest. 2017 Feb;151(2):468-480. doi: 10.1016/j.chest.2016.05.024. Epub 2016 Jun 2. — View Citation

Kim DY, Kim HJ, Han KH, Han SY, Heo J, Woo HY, Um SH, Kim YH, Kweon YO, Lim HY, Yoon JH, Lee WS, Lee BS, Lee HC, Ryoo BY, Yoon SK. Real-Life Experience of Sorafenib Treatment for Hepatocellular Carcinoma in Korea: From GIDEON Data. Cancer Res Treat. 2016 — View Citation

Kudo M, Ikeda M, Takayama T, Numata K, Izumi N, Furuse J, Okusaka T, Kadoya M, Yamashita S, Ito Y, Kokudo N. Safety and efficacy of sorafenib in Japanese patients with hepatocellular carcinoma in clinical practice: a subgroup analysis of GIDEON. J Gastroe — View Citation

Simonneau G, D'Armini AM, Ghofrani HA, Grimminger F, Jansa P, Kim NH, Mayer E, Pulido T, Wang C, Colorado P, Fritsch A, Meier C, Nikkho S, Hoeper MM. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary — View Citation

Wang C, Jing ZC, Huang YG, Zhou DX, Liu ZH, Meier C, Nikkho S, Curram J, Zhang P, He JG. Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison. Heart Asia. 2016 May 17;8(1):74-82. doi: 10.1136/heartasia-2015-01071 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	All Caused Mortality	All cause mortality (including cardiovascular mortality) was one component of the composite endpoint "time to clinical worsening".	At visit 6 (week 16)
Other	Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16	Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.	Baseline and week 16
Other	Cardiac Index (CI) - Change From Baseline to Week 16	The cardiac index (CI) is a calculated hemodynamic parameter. CI is derived from the directly measured parameters cardiac output (CO), divided by the body surface area (BSA). BSA is a calculated parameter, using the subject's height and weight in the DuBois formula. Formula: BSA = (W [kg]*0.425)*(H [cm]*0.725)*0.007184 (m^2)	Baseline and week 16
Other	Systolic Blood Pressure (SBP) - Change From Baseline to Week 16	Systolic systemic arterial blood pressure (SBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 95 - 180 mmHg.	Baseline and week 16
Other	Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16	Diastolic systemic arterial blood pressure (DBP) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: <= 110 mmHg.	Baseline and week 16
Other	Heart Rate (HR) - Change From Baseline to Week 16	Heart rate (HR) is a directly non-invasively measured hemodynamic parameter. Range allowed in this study at Visit 0 and/or Visit 1 before randomization: 50 -105 beats per minute (bpm) at rest.	Baseline and week 16
Other	Alanine Aminotransferase (ALT) - Change From Baseline to Week 16	Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L.	Baseline and week 16
Other	Aspartate Aminotransferase (AST) - Change From Baseline to Week 16	Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L.	Baseline and week 16
Other	Alkaline Phosphatase (AP) - Change From Baseline to Week 16	Alkaline phosphatase (AP) is a standard clinical chemistry parameter. Normal range: 40 to 129 U/L (males), 35 to 104 U/L (females)	Baseline and week 16
Other	Bilirubin - Change From Baseline to Week 16	Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL	Baseline and week 16
Other	Creatinine - Change From Baseline to Week 16	Creatinine is a standard clinical chemistry parameter. Normal range: 0.25 to 1.20 mg/dL (males), 0.46 to 1.00 mg/dL (females)	Baseline and week 16
Other	Creatinine Clearance - Change From Baseline to Week 16	Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females)	Baseline and week 16
Other	Creatine Kinase (CK) - Change From Baseline to Week 16	Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females)	Baseline and week 16
Other	Erythrocytes (RBC) - Change From Baseline to Week 16	Erythrocytes (red blood cells, RBC) is a standard clinical hematology parameter. Normal range: 4.6 to 5.8*10^12 cells/L (males), 4.1 to 5.2*10^12 cells/L (females)	Baseline and week 16
Other	Leukocytes (WBC) - Change From Baseline to Week 16	Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7*10^9 cells/L	Baseline and week 16
Other	Lymphocytes - Change From Baseline to Week 16	Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0*10^9 cells/L	Baseline and week 16
Other	Neutrophils - Change From Baseline to Week 16	Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4*10^9 cells/L	Baseline and week 16
Other	Hemoglobin - Change From Baseline to Week 16	Hemoglobin is a standard clinical hematology parameter. Normal range: 13.5 to 17.5 g/dL (males), 12.0 to 16.0 g/dL (females)	Baseline and week 16
Other	Hematocrit - Change From Baseline to Week 16	Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females)	Baseline and week 16
Other	Potassium - Change From Baseline to Week 16	Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L	Baseline and week 16
Other	Urate - Change From Baseline to Week 16	Urate is a standard clinical chemistry parameter. Normal range: 4.0 to 8.5 mg/dL (males, 16-59 years), 3.4 to 8.7 mg/dL (males, >60 years) 2.5 to 7.5 mg/dL (females)	Baseline and week 16
Other	Urea (BUN) - Change From Baseline to Week 16	Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL	Baseline and week 16
Other	Cystatin C - Change From Baseline to Week 16	Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL	Baseline and week 16
Other	Triacylglycerol Lipase - Change From Baseline to Week 16	Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L	Baseline and week 16
Other	Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16	Arterial partial pressure of carbon dioxide (PaCO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.	Baseline and week 16
Other	Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16	Arterial partial pressure of oxygen (PaO2) is performed as part of the capillary or arterial blood gas analysis. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.	Baseline and week 16
Other	Oxygen Saturation (SaO2) - Change From Baseline to Week 16	Oxygen saturation (SaO2) is measured as part of the capillary or arterial blood gas analysis. Normal blood oxygen saturation is considered 95-100 percent. If possible, no supplementary oxygen was given during the resting period and while blood samples were drawn.	Baseline and week 16
Other	Mean PR Duration (PRmean) - Change From Baseline to Week 16	PR duration was evaluated as part of the 12-lead electrocardiogram. electrocardiograms (ECGs) were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean QRS Duration (QRSmean) - Change From Baseline to Week 16	QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean QT Duration (QTmean) - Change From Baseline to Week 16	QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16	Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16	Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean RR Duration (RRmean) - Change From Baseline to Week 16	RR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.	Baseline and week 16
Other	Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16	Ventricular rate was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position	Baseline and week 16
Primary	6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16	6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity.	Baseline and week 16
Secondary	Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16	The pulmonary vascular resistance (PVR) is a calculated hemodynamic parameter. PVR is derived from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP), divided by the cardiac output (CO). PVR and PAPmean are acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: PVR = 80*(PAPmean - PCWP)/CO	Baseline and week 16
Secondary	N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16	N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the blood are used for screening, diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure.	Baseline and week 16
Secondary	World Health Organization (WHO) Functional Class - Change From Baseline to Week 16	The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (Patients with PH but without resulting limitation of physical activity) to class IV (Patients with PH with inability to carry out any physical activity without symptoms. These patients manifest signs of right-heart failure.). Changes to a lower WHO functional class resemble improvement; changes to a higher functional class resemble deterioration of PAH.	Baseline and week 16
Secondary	Percentage of Participants With Clinical Worsening	The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; rescue endarterectomy; first hospitalization due to pulmonary hypertension; start of a new pulmonary hypertension treatment; persistent worsening of 6MWD or WHO functional class due to deterioration of PH.	At week 16
Secondary	Borg CR 10 Scale - Change From Baseline to Week 16	The Borg CR10 Scale is a participant reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the participant's exertion during a physical test. Low values indicate low levels of exertion; high values indicate more intense exertion reported by the participant. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal").	Baseline and week 16
Secondary	EQ-5D Utility Score - Change From Baseline to Week 16	EQ-5D utility score is a Quality-of-Life participant reported outcome measure. The utility score is calculated based on five questions concerning problems with mobility, self-care, usual activities, pain/discomfort and anxiety/depression. An increase in the utility score represents an improvement in quality of life. The score ranges from -0.594 (worst answer in all five questions) to 1 (best answer in all five questions).	Baseline and week 16
Secondary	Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16	The self-reported Living with Pulmonary Hypertension (LPH) questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH total score can range from 0 (best) to 105 (worst).	Baseline and week 16