A Study to Evaluate Efficacy and Safety of Oral BAY63-2521 in Patients With Pulmonary Arterial Hypertension (PAH) (PATENT-1)

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

Tracking Information

• First Submitted Date: December 17, 2008
• First Posted Date: December 18, 2008
• Results First Submitted Date: November 5, 2013
• Results First Posted Date: February 26, 2014
• Last Update Posted Date: November 28, 2016
• Study Start Date: December 2008
• Actual Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 24, 2014)

6 Minutes Walking Distance (6MWD) - Change From Baseline to Week 12 [ Time Frame: Baseline and week 12 ]

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

• Original Primary Outcome Measures (submitted: December 17, 2008): 6 minute Walking Distance [ Time Frame: after 12 weeks ]
• Change History: Complete list of historical versions of study NCT00810693 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: January 24, 2014)

• Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 12 [ Time Frame: Baseline and week 12 ]
  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 12 [ Time Frame: Baseline and week 12 ]
  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 12 [ Time Frame: Baseline and week 12 ]
  The WHO functional assessment of pulmonary arterial hypertension ranged from functional class I (participants with PH but without resulting limitation of physical activity) to class IV (participants with PH with inability to carry out any physical activity without symptoms. These participants 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 12 ]
  The combined endpoint "time to clinical worsening", made up of the following components, defined by the first occurrence: all-cause mortality; heart/lung transplantation; atrial septostomy; 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 12 [ Time Frame: Baseline and week 12 ]
  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 12 [ Time Frame: Baseline and week 12 ]
  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 12 [ Time Frame: Baseline and week 12 ]
  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: December 17, 2008)

• Change from baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: after 12 weeks ]
• Change from baseline in NT-pro BNP [ Time Frame: after 12 weeks ]
• Change from baseline in WHO functional class [ Time Frame: after 12 weeks ]
• Time To Clinical Worsening [ Time Frame: after 12 weeks ]
• Change from baseline in Borg Dyspnoea Score [ Time Frame: after 12 weeks ]
• Change from baseline in EQ-5D visual analogue scale [ Time Frame: after 12 weeks ]
• Health Economics questionnaries [ Time Frame: after 12 weeks ]

• Current Other Pre-specified Outcome Measures: Not Provided
• 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 Pulmonary Arterial Hypertension (PAH)
• 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 Symptomatic Pulmonary Arterial Hypertension (PAH)
• Brief Summary: The aim of the study is to assess the efficacy and safety of different doses of BAY63-2521 given orally for 12 weeks, in patients with symptomatic Pulmonary Arterial Hypertension (PAH).
• Detailed Description: Not Provided
• 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: 1mg tid - 2.5mg tid orally for 12 weeks
• Drug: Riociguat (Adempas, BAY63-2521)
  BAY63-2521: 1.5mg tid orally for 12 weeks
• Drug: Placebo
  Matching Placebo tid orally for 12 weeks

Study Arms

• Experimental: Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT
  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 12 weeks
  Intervention: Drug: Riociguat (Adempas, BAY63-2521)
• Experimental: Riociguat (Adempas, BAY63-2521) up to 1.5 mg_IDT
  Participants received Riociguat orally as a film-coated tablet up to 1.5mg three times daily (tid) (titration between 1.0 mg and 1.5 mg tid based on an individual dose titration (IDT) scheme) for 12 weeks
  Intervention: Drug: Riociguat (Adempas, BAY63-2521)
• Placebo Comparator: Placebo
  Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks
  Intervention: Drug: Placebo

Publications *

• 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.
• Ghofrani HA, Galiè N, Grimminger F, Grünig 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.
• 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.
• 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.
• 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, 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: March 6, 2012): 445
• Original Estimated Enrollment (submitted: December 17, 2008): 462
• Actual Study Completion Date: May 2012
• Actual Primary Completion Date: May 2012 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Male and female patients with symptomatic PAH (Idiopathic, Familial, Associated PAH due to connective tissue disease, congenital heart disease, portal hypertension with liver cirrhosis, or due to anorexigen or amphetamine use)
• Treatment naive patients and patients pre-treated with an Endothelin Antagonist or a Prostacyclinanalogue (except I.V.).

Exclusion Criteria:

• All types of pulmonary hypertension except subtypes of Venice Group I specified in the inclusion criteria, severe COPD (chronic obstructive pulmonary disease), uncontrolled arterial hypertension, left heart failure.

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

Administrative Information

• NCT Number: NCT00810693
• Other Study ID Numbers: 12934; 2008-003482-68 ( 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