BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension (PATENT-2)

Long-term Extension, Multicentre, Multi-national Study to Evaluate the Safety and Tolerability of Oral BAY63-2521 (1mg,1.5 mg, 2.0 mg, 2.5 mg Tid) in Patients With Symptomatic Pulmonary Arterial Hypertension (PAH)

Patients who have completed the 12 weeks treatment of the PATENT-1 trial (study number 12934) will be asked to participate in this long term extension study with BAY63-2521.

Study Overview

• Status: Completed
• Conditions: Hypertension, Pulmonary
• Intervention / Treatment: Drug: Riociguat (BAY63-2521)

• Study Type: Interventional
• Enrollment (Actual): 396
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Capital Federal, Argentina
• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
    • Herston, Queensland, Australia, 4029
  • Tasmania
    • Hobart, Tasmania, Australia, 7000
  • Victoria
    • Prahran, Victoria, Australia, 3181
• Austria
  • Innsbruck, Austria, 6020
  • Wien, Austria, 1090
  • Oberösterreich
    • Linz, Oberösterreich, Austria, 4020
• Belgium
  • Bruxelles - Brussel, Belgium, 1070
  • Leuven, Belgium, 3000
• Brazil
  • Rio de Janeiro, Brazil, 21941-913
  • Rio Grande Do Sul
    • Porto Alegre, Rio Grande Do Sul, Brazil, 90020 090
  • Sao Paulo
    • São Paulo, Sao Paulo, Brazil, 04012 180
    • São Paulo, Sao Paulo, Brazil, 04020-050
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
• China
  • Beijing, China, 100020
  • Beijing, China, 100037
  • Shanghai, China, 200032
  • Shanghai, China, 200433
  • Guangdong
    • Guangzhou, Guangdong, China, 510100
• Czechia
  • Praha 2, Czechia, 12808
• Denmark
  • Aarhus N, Denmark, 8200
• France
  • Besancon, France, 25030
  • Brest, France, F-29609
  • GRENOBLE Cedex 09, France, 38043
  • Lille Cedex, France, 59037
  • Montpellier, France, 34059
  • Pessac, France, 33604
  • Rouen, France, 76031
• Germany
  • Baden-Württemberg
    • Heidelberg, Baden-Württemberg, Germany, 69126
  • Bayern
    • München, Bayern, Germany, 81377
  • Hessen
    • Gießen, Hessen, Germany, 35392
  • Mecklenburg-Vorpommern
    • Greifswald, Mecklenburg-Vorpommern, Germany, 17475
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
  • Nordrhein-Westfalen
    • Köln, Nordrhein-Westfalen, Germany, 50924
  • Saarland
    • Homburg, Saarland, Germany, 66421
  • Sachsen
    • Dresden, Sachsen, Germany, 01307
    • Leipzig, Sachsen, Germany, 04103
• Greece
  • Chaidari, Greece, 124 62
• Italy
  • Friuli-Venezia Giulia
    • Trieste, Friuli-Venezia Giulia, Italy, 34149
  • Lazio
    • Roma, Lazio, Italy, 00161
  • Lombardia
    • Milano, Lombardia, Italy, 20123
    • Pavia, Lombardia, Italy, 27100
• Japan
  • Hiroshima, Japan, 734-8551
  • Okayama, Japan, 701-1192
  • Aichi
    • Nagoya, Aichi, Japan, 467-8602
  • Hyogo
    • Kobe, Hyogo, Japan, 650-0017
  • Ibaraki
    • Toride, Ibaraki, Japan, 302-0022
    • Tsukuba, Ibaraki, Japan, 305-8576
  • Ishikawa
    • Kanazawa, Ishikawa, Japan, 920-8641
  • Miyagi
    • Sendai, Miyagi, Japan, 980-8574
  • Okinawa
    • Tomigusuku, Okinawa, Japan, 901-0243
  • Tokyo
    • Bunkyo-ku, Tokyo, Japan, 113-8655
    • Mitaka, Tokyo, Japan, 181-8611
    • Ota-ku, Tokyo, Japan, 143-8541
    • Shinjuku-ku, Tokyo, Japan, 160-8582
• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
  • Seoul, Korea, Republic of, 06351
  • Seoul, Korea, Republic of, 03722
• Mexico
  • Mexico D.F., Mexico, 14080
  • Querétaro, Mexico, 38000
  • Jalisco
    • Guadalajara, Jalisco, Mexico, 44280
      • Antiguo Hospital Civil de Guadalajara "Fray Antonio Alcalde"
    • Guadalajara, Jalisco, Mexico, 44670
      • Pulmocritic
  • Nuevo Leon
    • Monterrey, Nuevo Leon, Mexico, 64020
  • Sinaloa
    • Culiacan, Sinaloa, Mexico, 80020
• Poland
  • Otwock, Poland, 05-400
• Portugal
  • Coimbra, Portugal, 3000-075
  • Lisboa, Portugal, 1169-024
  • Lisboa, Portugal, 1649-035
    • Centro Hospitalar de Lisboa Norte - Hospital Santa Maria
• Russian Federation
  • Moscow, Russian Federation, 121552
  • St. Petersburg, Russian Federation, 197341
• Singapore
  • Singapore, Singapore, 119228
  • Singapore, Singapore, 168752
• Sweden
  • Umeå, Sweden, 901 85
• Switzerland
  • Zürich, Switzerland, 8091
• Taiwan
  • Kaohsiung City, Taiwan, 813414
  • Taipei, Taiwan, 100
  • Taipei, Taiwan, 11217
• Thailand
  • Bangkok, Thailand, 10330
  • Chiang Mai, Thailand, 50200
• Turkey
  • Ankara, Turkey
  • Istanbul, Turkey, 34098
  • Izmir, Turkey, 35-100
• United Kingdom
  • London, United Kingdom, NW3 2QG
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
  • West Dunbartonshire
    • Clydebank, West Dunbartonshire, United Kingdom, G81 4DY
• United States
  • California
    • Los Angeles, California, United States, 90073
    • Sacramento, California, United States, 95817
  • Colorado
    • Aurora, Colorado, United States, 80045
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
    • Boston, Massachusetts, United States, 02114
  • Nebraska
    • Omaha, Nebraska, United States, 68131
  • Ohio
    • Cleveland, Ohio, United States, 44195
    • Columbus, Ohio, United States, 43221
    • Fairfield, Ohio, United States, 45014
  • Texas
    • Dallas, Texas, United States, 75390-9252
    • El Paso, Texas, United States, 79902

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients who have completed 12 weeks of treatment in the double blind trial PATENT 1

Exclusion Criteria:

• Patients who have an ongoing serious adverse event from PATENT 1 that is assessed as related to BAY63-2521 are not allowed to participate in the extension trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1	Drug: Riociguat (BAY63-2521); BAY63-2521: 1mg tid -2.5 mg tid oral until end of study

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment-emergent Adverse Events (TEAE)	Analyses of drug-related TEAEs were based on the assessment of causal relationship to study medication.	From administration of first dose of study medication in PATENT-2 up to 2 days after end of treatment with study medication, up to 10 years and 5 months.
Number of Participant With Death	Analyses of deaths were based on the assessment of causal relationship to study medication. The safety follow-up visit was to be performed 30 days after the last dose of riociguat.	From baseline to end of safety follow-up visit, up to 10 years and 6 months (1 month more than End of study visit)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Hematology and Coagulation	Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Hematology and Coagulation	Percentage of participants only with a treatment-emergent shift in hematology and coagulation parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Clinical Chemistry	Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or low at baseline to a high value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or low value at baseline who had at least one high value after the start of treatment with the number of participants with a normal or low value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Clinical Chemistry	Percentage of participants per treatment group only with a treatment-emergent shift in clinical chemistry parameters from normal or high at baseline to a low value at a timepoint after the start of treatment. The percentage was calculated by comparing the number of participants with a normal or high value at baseline who had at least one low value after the start of treatment with the number of participants with a normal or high value at baseline who also had at least one valid value after start of treatment. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of Systolic Blood Pressure (SBP)	SBP was measured after the participant had been at rest for 10 minutes in a supine position. Low SBP was defined as SBP <95 mmHg, normal SBP as SBP 95-140mmHg, and high SBP as SBP >140 mmHg. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Diastolic Blood Pressure (DBP)	DBP was measured after the participants had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Heart Rate	Heart rate was measured after the participant had been at rest for 10 minutes in a supine position. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Weight	Weight was evaluated for safety. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Oxygen Saturation (SaO2)	SaO2 is one parameters of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Arterial Partial Oxygen Pressure (PaO2)	PaO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of Arterial Partial Pressure of Carbon Dioxide (PaCO2)	PaCO2 is one parameter of blood gas. The sample was obtained with the participant resting in a sitting or supine position for at least 10 minutes. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to termination visit, up to 10 years
Change of RR Duration From Electrocardiogram (ECG)	Heart rate from ECG is derived from the RR duration, unless arrhythmias such as atrial fibrillation or ventricular extra beats require additional calculations. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.	From baseline to Month 48
Change of PR Duration From ECG	PR duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.	From baseline to Month 48
Change of QRS Duration From ECG	QRS duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.	From baseline to Month 48
Change of QT Duration in ECG	QT duration was evaluated as part of ECG. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position. Analyses up to Month 48. After this timepoint, data was available for considerably fewer participants in the analysis set.	From baseline to Month 48
Change in Six-minute Walking Distance (6MWD) Test	6MWD is exercise testing and is one of efficacy evaluation	From baseline to End of study visit, up to 10 years and 5 months.
Change in Pulmonary Vascular Resistance (PVR)	Pulmonary vascular resistance (PVR) was measured only if right-heart catheterization was performed as part of a regular diagnostic work-up. A termination visit was only to be performed in the case of premature termination of study medication or if the sponsor announced the official end of the study.	From baseline to Termination visit, up to 10 years 5 months
Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP)	NT-proBNP levels in the blood are used for diagnosis of acute congestive heart failure (CHF) and may be useful to establish prognosis in heart failure	From baseline to End of study visit, up to 10 year and 5 months
Change in World Health Organization (WHO) Functional Class	WHO classification: I: Participants with PH. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope. II: Participants with PH are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope. III: Participants with PH are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope. IV: Participants with PH with inability to carry out any physical activity. They manifest signs of right-heart failure. Dyspnea and/or fatigue may even be present at rest. For class change from baseline, minus indicates a participant's functional class decreased compared with baseline (e.g. "-1" indicates a participant changed from class IV to class III, or from class II to class I), plus indicates a participant's functional class increased compared with baseline (e.g. "+1" indicates a participant changed from class I to class II, or from class III to class IV).	From baseline to End of study visit, up to 10 years and 5 months.
Number of Participants With Clinical Worsening	Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)	From baseline to End of study visit, up to 10 years and 5 months.
Incidence of Clinical Worsening Events Per 100 Person Years	Time to clinical worsening was a parameter that combined death and events reflective of persistent clinical worsening of the participant's underlying diagnosis of pulmonary hypertension (PH)	From baseline to End of study visit, up to 10 years and 5 months.
Change From Baseline in Borg CR 10 Scale	The Borg CR10 Scale was measured in conjunction with the 6MWD test. The test was explained to the participant before starting the 6MWD test. Participants were asked to rank their exertion at the end of the 6MWD 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")	From baseline to Week 12
Change in Score of EQ-5D Questionnaire	The EQ-5D is a standardized instrument for use as a measure of health outcome. The EQ-5D is a self report questionnaire. 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).	From baseline to End of study visit, up to 10 years and 5 months.
Change in Score of Living With Pulmonary Hypertension (LPH) Questionnaire	The LPH questionnaire is designed to measure the effects of PH and PH-specific treatments on an individual's quality of life. The LPH is a self-report questionnaire and was completed by the participant. The LPH total score can range from 0 (best) to 105 (worst).	From baseline to End of study visit, up to 10 years and 5 months.

Collaborators and Investigators

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

Publications and helpful links

General Publications

• 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.
• Benza RL, Ghofrani HA, Grunig E, Hoeper MM, Jansa P, Jing ZC, Kim NH, Langleben D, Simonneau G, Wang C, Busse D, Meier C, Ghio S. Effect of riociguat on right ventricular function in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant. 2021 Oct;40(10):1172-1180. doi: 10.1016/j.healun.2021.06.020. Epub 2021 Jul 10.
• Humbert M, Coghlan JG, Ghofrani HA, Grimminger F, He JG, Riemekasten G, Vizza CD, Boeckenhoff A, Meier C, de Oliveira Pena J, Denton CP. Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease: results from PATENT-1 and PATENT-2. Ann Rheum Dis. 2017 Feb;76(2):422-426. doi: 10.1136/annrheumdis-2015-209087. Epub 2016 Jul 25.
• Saleh S, Becker C, Frey R, Muck 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.
• 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 Heart Lung Transplant. 2022 Mar;41(3):411-420. doi: 10.1016/j.healun.2021.10.013. Epub 2021 Oct 28.
• 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.
• Ghofrani HA, Grimminger F, Grunig E, Huang Y, Jansa P, Jing ZC, Kilpatrick D, Langleben D, Rosenkranz S, Menezes F, Fritsch A, Nikkho S, Humbert M. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016 May;4(5):361-71. doi: 10.1016/S2213-2600(16)30019-4. Epub 2016 Apr 8.
• Rosenkranz S, Ghofrani HA, Beghetti M, Ivy D, Frey R, Fritsch A, Weimann G, Saleh S, Apitz C. Riociguat for pulmonary arterial hypertension associated with congenital heart disease. Heart. 2015 Nov;101(22):1792-9. doi: 10.1136/heartjnl-2015-307832. Epub 2015 Jul 1.
• Rubin LJ, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh A, Langleben D, Fritsch A, Menezes F, Davie N, Ghofrani HA. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015 May;45(5):1303-13. doi: 10.1183/09031936.00090614. Epub 2015 Jan 22.
• Ghofrani HA, Galie N, Grimminger F, Grunig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D, Rubin LJ; PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40. doi: 10.1056/NEJMoa1209655.

Helpful Links

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Study record dates

Study Major Dates

• Study Start (Actual): March 12, 2009
• Primary Completion (Actual): August 19, 2019
• Study Completion (Actual): August 19, 2019

Study Registration Dates

• First Submitted: March 13, 2009
• First Submitted That Met QC Criteria: March 17, 2009
• First Posted (Estimated): March 18, 2009

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Pulmonary arterial hypertension; PH; Stimulator
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension; Pulmonary Arterial Hypertension; Hypertension, Pulmonary; Molecular Mechanisms of Pharmacological Action; Enzyme Activators; Riociguat
• Other Study ID Numbers: 12935; 2008-003610-94 (EudraCT Number)

Drug and device information, study documents

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