A Study to Test the Effects of Riociguat in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction (LEPHT)

Randomized, Double Blind, Placebo Controlled, Parallel Group, Multi-center Study to Evaluate the Hemodynamic Effects of Riociguat (BAY 63-2521) as Well as Safety and Kinetics in Patients With Pulmonary Hypertension Associated With Left Ventricular Systolic Dysfunction

The aim of this study is to assess whether increasing oral doses of Riociguat are safe and improve the well-being, symptoms and outcome in patients with pulmonary hypertension associated with left ventricular systolic dysfunction

Study Overview

• Status: Active, not recruiting
• Conditions: Hypertension, Pulmonary; Ventricular Dysfunction, Left
• Intervention / Treatment: Drug: Riociguat (Adempas, BAY63-2521); Drug: Riociguat (Adempas, BAY63-2521); Drug: Riociguat (Adempas, BAY63-2521); Drug: Placebo

Detailed Description

Pharmacokinetics parameters were regarded as exploratory parameters. Adverse event data will be covered in Adverse events section.

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
  • Queensland
    • Chermside, Queensland, Australia, 4032
  • Victoria
    • Prahran, Victoria, Australia, 3181
• Austria
  • Wien, Austria, 1090
  • Tirol
    • Innsbruck, Tirol, Austria, 6020
• Belgium
  • Aalst, Belgium, 9300
  • Bruxelles - Brussel, Belgium, 1070
  • Gent, Belgium, 9000
  • Leuven, Belgium, 3000
• Canada
  • Quebec, Canada, G1V 4G5
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
• China
  • Beijing, China, 100020
  • Shanghai, China
  • Shanghai, China, 200433
• Czechia
  • Brno, Czechia, 656 91
  • Olomouc, Czechia, 779 00
  • Praha 2, Czechia, 12808
  • Praha 4, Czechia, 140 21
• Denmark
  • Aarhus N, Denmark, 8200
• France
  • Bron, France, 69500
  • Lille Cedex, France, 59037
  • Nantes, France, 44035
  • Pessac, France, 33604
  • Rouen, France, 76031
  • Toulouse, France, 31403
• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69120
  • Bayern
    • Augsburg, Bayern, Germany, 86156
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 50924
  • Thüringen
    • Erfurt, Thüringen, Germany, 99089
• Italy
  • Campania
    • Napoli, Campania, Italy, 80131
  • Lombardia
    • Pavia, Lombardia, Italy, 27100
• Japan
  • Osaka, Japan, 530-8480
  • Osaka, Japan, 541-8567
  • Aichi
    • Nagoya, Aichi, Japan, 466-8560
    • Seto, Aichi, Japan, 489-8642
  • Gifu
    • Ogaki, Gifu, Japan, 503-8502
  • Ibaraki
    • Higashiibaraki, Ibaraki, Japan, 311-3193
  • Mie
    • Tsu, Mie, Japan, 514-1101
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
  • Osaka
    • Suita, Osaka, Japan, 565-0871
  • Shiga
    • Kusatsu, Shiga, Japan, 525-8585
  • Shizuoka
    • Sunto, Shizuoka, Japan, 411-8611
  • Tokyo
    • Arakawa-ku, Tokyo, Japan, 116-8567
    • Shinjuku-ku, Tokyo, Japan, 162-8666
  • Wakayama
    • Tanabe, Wakayama, Japan, 646-8558
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
  • Amsterdam, Netherlands, 1091 AC
  • Nijmegen, Netherlands, 6500HB
• Poland
  • Bydgoszcz, Poland, 85-168
  • Gdansk, Poland, 80-214
  • Warszawa, Poland, 04-628
• Singapore
  • Singapore, Singapore, 119228
  • Singapore, Singapore, 168752
  • Singapore, Singapore, 308433
• Spain
  • A Coruña, Spain, 15006
  • Barcelona, Spain, 08003
  • Madrid, Spain, 28041
  • Valencia, Spain, 46026
  • Madrid
    • Majadahonda, Madrid, Spain, 28222
  • Murcia
    • El Palmar, Murcia, Spain, 30120
  • Palma De Mallorca
    • Palma, Palma De Mallorca, Spain, 07198
• Switzerland
  • Zürich, Switzerland, 8091
  • Genève
    • Geneva, Genève, Switzerland, 1205
  • Ticino
    • Lugano, Ticino, Switzerland, 6900
• United Kingdom
  • Cambridge, United Kingdom, CB23 3RE
  • London, United Kingdom, SW3 6NP
• United States
  • California
    • Fountain Valley, California, United States, 92708
    • Los Angeles, California, United States, 90073
    • San Diego, California, United States, 92103
    • Torrance, California, United States, 90502
  • Florida
    • Miami, Florida, United States, 33136
  • Iowa
    • Iowa City, Iowa, United States, 52242
  • Maryland
    • Baltimore, Maryland, United States, 21201
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
  • Minnesota
    • Rochester, Minnesota, United States, 55905
  • Missouri
    • Saint Louis, Missouri, United States, 63110
  • Ohio
    • Cincinnati, Ohio, United States, 45219
    • Fairfield, Ohio, United States, 45014
  • Virginia
    • Falls Church, Virginia, United States, 22042
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients with symptomatic pulmonary hypertension due to left ventricular systolic dysfunction despite optimized heart failure therapy

Exclusion Criteria:

• Types of pulmonary hypertension other than group 2.1 of Dana Point Classification

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Riociguat (Adempas, BAY63-2521) up to 2 mg; Participants received riociguat up to 2 mg three times per day (tid) (increasing from 0.5 to 1 to 2 mg).	Drug: Riociguat (Adempas, BAY63-2521); up to 2 mg three times a day (increasing from 0.5 to 1 to 2 mg); Drug: Riociguat (Adempas, BAY63-2521); up to 1 mg three times a day (increasing from 0.5 to 1 mg); Drug: Riociguat (Adempas, BAY63-2521); fixed 0.5 mg three times a day
Experimental: Riociguat (Adempas, BAY63-2521) up to 1 mg; Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).	Drug: Riociguat (Adempas, BAY63-2521); up to 2 mg three times a day (increasing from 0.5 to 1 to 2 mg); Drug: Riociguat (Adempas, BAY63-2521); up to 1 mg three times a day (increasing from 0.5 to 1 mg); Drug: Riociguat (Adempas, BAY63-2521); fixed 0.5 mg three times a day
Experimental: Riociguat (Adempas, BAY63-2521) fixed 0.5 mg; Participants received riociguat 0.5 mg tid (fixed dose).	Drug: Riociguat (Adempas, BAY63-2521); up to 2 mg three times a day (increasing from 0.5 to 1 to 2 mg); Drug: Riociguat (Adempas, BAY63-2521); up to 1 mg three times a day (increasing from 0.5 to 1 mg); Drug: Riociguat (Adempas, BAY63-2521); fixed 0.5 mg three times a day
Placebo Comparator: Placebo; Participants received placebo tid.	Drug: Placebo; Placebo three times a day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulmonary Artery Mean Pressure (PAPmean) at Rest - 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 visit 6 (16 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Venous Oxygen Saturation (SvO2) - Change From Baseline to Week 16	The mixed venous oxygen saturation rate (SvO2) is a directly measured hemodynamic parameter. SvO2 is recorded during a right heart catheterization.	Baseline and visit 6 (16 weeks)
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 visit 6 (16 weeks)
Pulmonary Vascular Resistance Index (PVRi) - Change From Baseline to Week 16	The pulmonary vascular resistance index (PVRi) is a calculated hemodynamic parameter. PVRi is derived from the pulmonary vascular resistance (PVR) normalized by the body surface area (BSA). Formula: PVRi = 80*(PAPmean - PCWP)*BSA/CO	Baseline and visit 6 (16 weeks)
Systemic Vascular Resistance (SVR) - Change From Baseline to Week 16	The systemic vascular resistance (SVR) is a calculated hemodynamic parameter. SVR is derived from the directly measured parameter mean right atrial pressure (RAPmean) and the calculated parameter mean systemic arterial pressure (SAPmean) divided by the cardiac output (CO). RAPmean is acquired during a right heart catheterization. CO is a calculated hemodynamic parameter, too. Formula: SVR = 80*(SAPmean - RAPmean)/CO	Baseline and visit 6 (16 weeks)
Systemic Vascular Resistance Index (SVRi) - Change From Baseline to Week 16	The systemic vascular resistance index (SVRi) is a calculated hemodynamic parameter. SVRi is derived from the systemic vascular resistance (SVR) normalized by the body surface area (BSA). Formula: SVRi = 80*(SAPmean - RAPmean)*BSA/CO	Baseline and visit 6 (16 weeks)
Transpulmonary Pressure Gradient (TPG) - Change From Baseline to Week 16	The transpulmonary pressure gradient (TPG) is a calculated hemodynamic parameter. TPG is calculated from the directly measured parameters mean pulmonary arterial pressure (PAPmean) and pulmonary capillary wedge pressure (PCWP). These 2 parameters are acquired during a right heart catheterization. Formula: TPG = PAPmean - PCWP	Baseline and visit 6 (16 weeks)
Pulmonary Capillary Wedge Pressure (PCWP) - Change From Baseline to Week 16	Pulmonary capillary wedge pressure (PCWP) is a directly measured hemodynamic parameter acquired during a right heart catheterization.	Baseline and visit 6 (16 weeks)
Tricuspid Annular Plane Systolic Excursion (TAPSE) - Change From Baseline to Week 16	The tricuspid annular plane systolic excursion (TAPSE) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.	Baseline and visit 6 (16 weeks)
Systolic Pulmonary Arterial Pressure (PAPsyst) - Change From Baseline to Week 16	Systolic pulmonary arterial pressure (PAPsyst) is a directly measured hemodynamic parameter acquired during a right heart catheterization.	Baseline and visit 6 (16 weeks)
Left Ventricular Ejection Fraction (LVEF) - Change From Baseline to Week 16	The left ventricular ejection fraction work index (LVEF) is a calculated echocardiography parameter. LVEF is derived from the directly measured parameters left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). These 2 parameters are acquired during a non-invasive echocardiography examination. Formula: LEVF = 100*(LVEDV - LVESV)/LVEDV	Baseline and visit 6 (16 weeks)
Left Ventricular End-systolic Volume (LVESV) - Change From Baseline to Week 16	Left ventricular end-systolic volume (LVESV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.	Baseline and visit 6 (16 weeks)
Left Ventricular End-diastolic Volume (LVEDV) - Change From Baseline to Week 16	Left ventricular end-diastolic volume (LVEDV) is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.	Baseline and visit 6 (16 weeks)
E-wave Deceleration Time - Change From Baseline to Week 16	E-wave deceleration time is a measured echocardiography parameter. It is acquired during a non-invasive echocardiography examination.	Baseline and visit 6 (16 weeks)
Ratio of Mitral Peak Velocity of Early Filling to Mitral Peak Velocity of Late Filling (E/A) - Change From Baseline to Week 16	E/A ratio is a measured echocardiography parameter and describes the ratio of mitral peak velocity of early filling to mitral peak velocity of late filling. It is acquired during a non-invasive echocardiography examination.	Baseline and visit 6 (16 weeks)
6-minute Walking Distance (6MWD) - Change From Baseline to Week 16	6-minute walking distance (6MWD) is a measure for the objective evaluation of a patient's functional exercise capacity.	Baseline and visit 6 (16 weeks)
WHO (World Health Organization) 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 visit 6 (16 weeks)
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, including cardiovascular mortality; first hospitalization for a cardiovascular event, including heart failure, acute myocardial infarction, stroke or ventricular arrhythmia; upgrade of the HTx (heart transplantation) status to next higher level; need for IV diuretics; persistent worsening of WHO functional class due to deterioration of PH or cardiac function.	At visit 6 (16 weeks)
Borg CR 10 Scale - Change From Baseline to Week 16	The Borg CR10 Scale is a patient reported outcome measure used in clinical diagnosis of e.g. breathlessness and dyspnea. It documents the patient's exertion during a physical test. Low values indicate low levels of exertion, high values indicate more intense exertion reported by the patient. The score ranges from 0 ("Nothing at all") to 10 ("Extremely strong - Maximal").	Baseline and visit 6 (16 weeks)
EQ-5D Utility Score - Change From Baseline to Week 16	EQ-5D utility score is a Quality-of-Life patient reported outcome measure. An increase in the utility score represents an improvement in quality of life. The score ranges from 0 (worst imaginable health state) to 100 (best imaginable health state).	Baseline and visit 6 (16 weeks)
Minnesota Living With Heart Failure Questionnaire (MLHF) Score - Change From Baseline to Week 16	The self-reported Minnesota Living with Heart Failure questionnaire (MLHF) is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The MLHF total score can range from 0 (best) to 105 (worst).	Baseline and visit 6 (16 weeks)
Cystatin C - Change From Baseline to Week 16	Cystatin C is a biomarker for predicting new onset or deteriorating cardiovascular disease.	Baseline and visit 6 (16 weeks)
N-terminal Pro-brain Natriuretic Peptide (NT-pro BNP) - Change From Baseline to Week 16	N-terminal pro-brain natriuretic peptide (NT-pro BNP) 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 visit 6 (16 weeks)
Troponin T - Change From Baseline to Week 16	Troponin T is a cardiac-specific protein which is released from damaged or injured heart muscle cells.	Baseline and visit 6 (16 weeks)
Asymmetric Dimethylarginine (ADMA) - Change From Baseline to Week 16	Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxides. Recent clinical studies have indicated that ADMA may have diagnostic relevance as a novel cardiovascular risk marker.	Baseline and visit 6 (16 weeks)
Osteopontin - Change From Baseline to Week 16	Osteopontin is a cytokine-like pro-fibrotic mediator, which is expressed in cardiovascular tissues. Its expression is induced by increased pressure and volume load in the myocardium, kidney and lung. Therefore, osteopontin may be used as a prognostic marker in patients with cardiovascular diseases.	Baseline and visit 6 (16 weeks)

Collaborators and Investigators

• Sponsor: Bayer
• Investigators: Study Director: Bayer Study Director, Bayer

Publications and helpful links

General Publications

• Ghio S, Bonderman D, Felix SB, Ghofrani HA, Michelakis ED, Mitrovic V, Oudiz RJ, Frey R, Roessig L, Semigran MJ. Left ventricular systolic dysfunction associated with pulmonary hypertension riociguat trial (LEPHT): rationale and design. Eur J Heart Fail. 2012 Aug;14(8):946-53. doi: 10.1093/eurjhf/hfs071. Epub 2012 Jun 20.
• Bonderman D, Ghio S, Felix SB, Ghofrani HA, Michelakis E, Mitrovic V, Oudiz RJ, Boateng F, Scalise AV, Roessig L, Semigran MJ; Left Ventricular Systolic Dysfunction Associated With Pulmonary Hypertension Riociguat Trial (LEPHT) Study Group. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation. 2013 Jul 30;128(5):502-11. doi: 10.1161/CIRCULATIONAHA.113.001458. Epub 2013 Jun 17.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2010
• Primary Completion (Actual): June 6, 2012
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: February 8, 2010
• First Submitted That Met QC Criteria: February 8, 2010
• First Posted (Estimated): February 9, 2010

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Pulmonary Hypertension; Left ventricular dysfunction
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Hypertension, Pulmonary; Ventricular Dysfunction; Ventricular Dysfunction, Left; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 14308; 2009-015878-35 (EudraCT Number); 2023-507001-34-00 (Other Identifier: CTIS (EU))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Availability of this study's data will later be determined according to Bayer's commitment to the EFPIA/PhRMA "Principles for responsible clinical trial data sharing". This pertains to scope, timepoint and process of data access. As such, Bayer commits to sharing upon request from qualified researchers patient-level clinical trial data, study-level clinical trial data, and protocols from clinical trials in patients for medicines and indications approved in the US and EU as necessary for conducting legitimate research. This applies to data on new medicines and indications that have been approved by the EU and US regulatory agencies on or after January 01, 2014.

Interested researchers can use www.vivli.org to request access to anonymized patient-level data and supporting documents from clinical studies to conduct research. Information on the Bayer criteria for listing studies and other relevant information is provided in the member section of the portal.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No