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

• ClinicalTrials.gov Identifier: NCT00863681
• Recruitment Status: Completed
• First Posted: March 18, 2009
• Results First Posted: October 22, 2020
• Last Update Posted: October 22, 2020
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Tracking Information

• First Submitted Date: March 13, 2009
• First Posted Date: March 18, 2009
• Results First Submitted Date: August 17, 2020
• Results First Posted Date: October 22, 2020
• Last Update Posted Date: October 22, 2020
• Actual Study Start Date: March 12, 2009
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 29, 2020)

• Number of Participants With Treatment-emergent Adverse Events (TEAE) [ Time Frame: 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. ]
  Analyses of drug-related TEAEs were based on the assessment of causal relationship to study medication.
• Number of Participant With Death [ Time Frame: From baseline to end of safety follow-up visit, up to 10 years and 6 months (1 month more than End of study visit) ]
  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.

• Original Primary Outcome Measures (submitted: March 17, 2009): Safety (adverse events collection) and tolerability [ Time Frame: 3 years ]

Current Secondary Outcome Measures (submitted: September 29, 2020)

• Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Hematology and Coagulation [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Hematology and Coagulation [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Percentage of Participants With Treatment-emergent High Laboratory Abnormalities in Clinical Chemistry [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Percentage of Participants With Treatment-emergent Low Laboratory Abnormalities in Clinical Chemistry [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.

• Original Secondary Outcome Measures (submitted: March 17, 2009): Change in 6MWD from baseline [ Time Frame: 3 years ]

Current Other Pre-specified Outcome Measures (submitted: September 29, 2020)

• Change of Systolic Blood Pressure (SBP) [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Diastolic Blood Pressure (DBP) [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Heart Rate [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Weight [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Oxygen Saturation (SaO2) [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Arterial Partial Oxygen Pressure (PaO2) [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of Arterial Partial Pressure of Carbon Dioxide (PaCO2) [ Time Frame: From baseline to termination visit, up to 10 years ]
  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.
• Change of RR Duration From Electrocardiogram (ECG) [ Time Frame: From baseline to Month 48 ]
  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.
• Change of PR Duration From ECG [ Time Frame: From baseline to Month 48 ]
  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.
• Change of QRS Duration From ECG [ Time Frame: From baseline to Month 48 ]
  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.
• Change of QT Duration in ECG [ Time Frame: From baseline to Month 48 ]
  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.
• Change in Six-minute Walking Distance (6MWD) Test [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  6MWD is exercise testing and is one of efficacy evaluation
• Change in Pulmonary Vascular Resistance (PVR) [ Time Frame: From baseline to Termination visit, up to 10 years 5 months ]
  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.
• Change in N-terminal Prohormone of Brain Natriuretic Peptide (NT-proBNP) [ Time Frame: From baseline to End of study visit, up to 10 year and 5 months ]
  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
• Change in World Health Organization (WHO) Functional Class [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  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).
• Number of Participants With Clinical Worsening [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  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)
• Incidence of Clinical Worsening Events Per 100 Person Years [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  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)
• Change From Baseline in Borg CR 10 Scale [ Time Frame: From baseline to Week 12 ]
  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")
• Change in Score of EQ-5D Questionnaire [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  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).
• Change in Score of Living With Pulmonary Hypertension (LPH) Questionnaire [ Time Frame: From baseline to End of study visit, up to 10 years and 5 months. ]
  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).

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: BAY63-2521:Long-term Extension Study in Patients With Pulmonary Arterial Hypertension
• Official Title: 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)
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Hypertension, Pulmonary

Intervention

Drug: Riociguat (BAY63-2521)

BAY63-2521: 1mg tid -2.5 mg tid oral until end of study

Study Arms

Experimental: Arm 1

Intervention: Drug: Riociguat (BAY63-2521)

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 16, 2012): 396
• Original Estimated Enrollment (submitted: March 17, 2009): 462
• Actual Study Completion Date: August 19, 2019
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

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, Czechia, Denmark, France, Germany, Greece, Italy, Japan, Korea, Republic of, Mexico, Poland, Portugal, Russian Federation, Singapore, Sweden, Switzerland, Taiwan, Thailand, Turkey, United Kingdom, United States
• Removed Location Countries: Czech Republic, Ireland, Israel, Netherlands, New Zealand, Slovakia, Spain

Administrative Information

• NCT Number: NCT00863681
• Other Study ID Numbers: 12935; 2008-003610-94 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Bayer
• Original Responsible Party: Therapeutic Area Head, Bayer Healthcare AG
• Current Study Sponsor: Bayer
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Bayer Study Director; Bayer

• PRS Account: Bayer
• Verification Date: September 2020