A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH. (CHEST-1)

• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: December 15, 2008
• First Posted Date: March 4, 2009
• Results First Submitted Date: November 4, 2013
• Results First Posted Date: March 11, 2014
• Last Update Posted Date: November 28, 2016
• Study Start Date: February 2009
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 25, 2014)

6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]

6-minute walking distance (6MWD) is a measure for the objective evaluation of a participant's functional exercise capacity.

• Original Primary Outcome Measures (submitted: March 3, 2009): 6 Minute Walking Distance [ Time Frame: 16 weeks ]
• Change History: Complete list of historical versions of study NCT00855465 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: January 25, 2014)

• Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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
• N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• World Health Organization (WHO) Functional Class - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Percentage of Participants With Clinical Worsening [ Time Frame: At week 16 ]
  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.
• Borg CR 10 Scale - Change From Baseline to Week 16 [ Time Frame: Baseline and 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").
• EQ-5D Utility Score - Change From Baseline to Week 16 [ Time Frame: Baseline and 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).
• Living With Pulmonary Hypertension (LPH) Questionnaire - Change From Baseline to Week 16 [ Time Frame: Baseline and 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).

Original Secondary Outcome Measures (submitted: March 3, 2009)

• Change from baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: 16 weeks ]
• Change from baseline in NT-pro BNP [ Time Frame: 16 weeks ]
• Change from baseline in WHO functional class [ Time Frame: 16 weeks ]
• Change from baseline in Borg Dyspnoea Score [ Time Frame: 16 weeks ]
• Time to clinical worsening [ Time Frame: 16 weeks ]
• Change from baseline in EQ-5D and LPH. [ Time Frame: 16 weeks ]
• Safety variables: adverse events, laboratory parameters, ECG, vital signs. [ Time Frame: 16 weeks ]

Current Other Pre-specified Outcome Measures (submitted: January 25, 2014)

• All Caused Mortality [ Time Frame: At visit 6 (week 16) ]
  All cause mortality (including cardiovascular mortality) was one component of the composite endpoint "time to clinical worsening".
• Mean Pulmonary Artery Pressure (PAPmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Mean pulmonary arterial pressure (PAPmean) is a directly measured hemodynamic parameter. PAPmean is recorded during a right heart catheterization.
• Cardiac Index (CI) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Systolic Blood Pressure (SBP) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Diastolic Blood Pressure (DBP) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Heart Rate (HR) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Alanine Aminotransferase (ALT) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Alanine Aminotransferase (ALT) is a standard clinical chemistry parameter. Normal range: 0 to 45 U/L.
• Aspartate Aminotransferase (AST) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Aspartate Aminotransferase (AST) is a standard clinical chemistry parameter. Normal range: 0 to 41 U/L.
• Alkaline Phosphatase (AP) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Bilirubin - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Bilirubin is a standard clinical chemistry parameter. Normal range: 0.1 to 1.2 mg/dL
• Creatinine - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Creatinine Clearance - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Creatinine clearance is a standard clinical chemistry parameter. Normal range: 90 to 140 mL/min (males), 80 to 125 mL/min (females)
• Creatine Kinase (CK) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Creatine Kinase is a standard clinical chemistry parameter. Normal range: 35 to 232 U/L (males), 26 to 145 U/L (females)
• Erythrocytes (RBC) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Leukocytes (WBC) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Leukocytes (white blood cells, WBC) is a standard clinical hematology parameter. Normal range: 4.0 to 10.7*10^9 cells/L
• Lymphocytes - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Total lymphocytes is a standard clinical hematology parameter. Normal range: 1.0 to 4.0*10^9 cells/L
• Neutrophils - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Neutrophils is a standard clinical hematology parameter. Normal range: 1.6 to 7.4*10^9 cells/L
• Hemoglobin - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Hematocrit - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Hematocrit is a standard clinical hematology parameter. Normal range: 40 to 52% (males), 36 to 46% (females)
• Potassium - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Potassium is a standard clinical chemistry parameter. Normal range: 3.5 to 5.3 mmol/L
• Urate - Change From Baseline to Week 16 [ Time Frame: Baseline and 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)
• Urea (BUN) - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Urea (blood urea nitrogen, BUN) is a standard clinical chemistry parameter. Normal range: 4 to 25 mg/dL
• Cystatin C - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Cystatin C is a biomarker. Normal range: 0.53 to 1.01 ng/mL
• Triacylglycerol Lipase - Change From Baseline to Week 16 [ Time Frame: Baseline and week 16 ]
  Triacylglycerol lipase is a standard clinical chemistry parameter. Normal range: 7 to 60 U/L
• Arterial Partial Pressure of Carbon Dioxide (PaCO2) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Arterial Partial Oxygen Pressure (PaO2) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Oxygen Saturation (SaO2) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean PR Duration (PRmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean QRS Duration (QRSmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean QT Duration (QTmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean RR Duration (RRmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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.
• Mean Ventricular Rate (VRmean) - Change From Baseline to Week 16 [ Time Frame: Baseline and 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

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With CTEPH.
• 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)
• Brief 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).
• Detailed Description: Adverse event data will be covered in Adverse events section.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Pulmonary Hypertension

Intervention

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

Study Arms

• Experimental: Riociguat (Adempas, BAY63-2521)_individual dose titration
  Participants received Riociguat orally as a film-coated tablet up to 2.5mg three times daily (tid) (titration between 1.0 mg and 2.5 mg tid based on an individual dose titration (IDT) scheme) for 16 weeks
  Intervention: Drug: Riociguat (Adempas, BAY63-2521)
• Placebo Comparator: Placebo
  Participants received Placebo orally as a film-coated tablet three times daily (tid) for 16 weeks
  Intervention: Drug: Placebo

Publications *

• 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. 2013 Jul 25;369(4):319-29. doi: 10.1056/NEJMoa1209657.
• 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.
• 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 hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016 May;4(5):372-80. doi: 10.1016/S2213-2600(16)30022-4. Epub 2016 Apr 8.
• 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-2015-010712. eCollection 2016.
• 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. Review.
• 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 Oct;48(4):1243-1252. Epub 2016 Feb 24.
• 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 Gastroenterol. 2016 Dec;51(12):1150-1160. Epub 2016 Apr 22.
• Kim NH, D'Armini AM, Grimminger F, Grünig E, Hoeper MM, Jansa P, Mayer E, Neurohr C, Simonneau G, Torbicki A, Wang C, Fritsch A, Davie N, Ghofrani HA. Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. Heart. 2017 Apr;103(8):599-606. doi: 10.1136/heartjnl-2016-309621. Epub 2016 Dec 23.
• Saleh S, Becker C, Frey R, Mück W. Population pharmacokinetics and the pharmacokinetic/pharmacodynamic relationship of riociguat in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulm Circ. 2016 Mar;6(Suppl 1):S86-96. doi: 10.1086/685404.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: January 25, 2014): 262
• Original Estimated Enrollment (submitted: March 3, 2009): 270
• Actual Study Completion Date: June 2012
• Actual Primary Completion Date: June 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 80 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, China, Czech Republic, Denmark, France, Germany, Ireland, Israel, Italy, Japan, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Russian Federation, Slovakia, Spain, Switzerland, Taiwan, Turkey, United Kingdom, United States

Administrative Information

• NCT Number: NCT00855465
• Other Study ID Numbers: 11348; 2007-000072-16 ( EudraCT Number )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Bayer
• Study Sponsor: Bayer
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: October 2016