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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT01065454
First received: February 8, 2010
Last updated: January 25, 2014
Last verified: January 2014
Results First Received: November 6, 2013  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Conditions: Hypertension, Pulmonary
Ventricular Dysfunction, Left
Interventions: Drug: Riociguat (Adempas, BAY63-2521)
Drug: Placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Only subjects with symptomatic pulmonary hypertension associated with left ventricular systolic dysfunction (PH-sLVD) could participate in this study. Subjects must have been pre-treated with optimized CHF therapy.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
301 subjects were enrolled in 84 study centers in 18 countries worldwide. 99 of the 301 enrolled subjects were not randomized (adverse event [1], protocol violation [1], screen failure [87], withdrawal by subject [10]). Of the 202 subjects randomized, one subject did not receive any study medication.

Reporting Groups
  Description
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).
Riociguat (Adempas, BAY63-2521) up to 1 mg Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Participants received riociguat 0.5 mg tid (fixed dose).
Placebo Participants received placebo tid.

Participant Flow for 2 periods

Period 1:   Treatment
    Riociguat (Adempas, BAY63-2521) up to 2 mg     Riociguat (Adempas, BAY63-2521) up to 1 mg     Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg     Placebo  
STARTED     67     33     32     69  
COMPLETED     54     28     23     57  
NOT COMPLETED     13     5     9     12  
Adverse Event                 7                 4                 3                 6  
Death                 1                 0                 0                 0  
Non-compliance                 1                 0                 0                 1  
Protocol Decision                 0                 0                 3                 2  
Protocol Violation                 1                 0                 1                 0  
Withdrawal by Subject                 3                 1                 2                 3  

Period 2:   Follow up
    Riociguat (Adempas, BAY63-2521) up to 2 mg     Riociguat (Adempas, BAY63-2521) up to 1 mg     Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg     Placebo  
STARTED     54     28     23     57  
Entering Follow-up     49     27     23     51  
COMPLETED     15     4     6     13  
NOT COMPLETED     39     24     17     44  
Adverse Event                 1                 0                 0                 1  
Death                 0                 1                 1                 0  
Lost to Follow-up                 0                 0                 0                 1  
Progressive disease                 0                 0                 0                 1  
Withdrawal by Subject                 1                 1                 1                 0  
study ongoing                 37                 22                 15                 41  



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
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).
Riociguat (Adempas, BAY63-2521) up to 1 mg Participants received riociguat up to 1 mg tid (increasing from 0.5 to 1 mg).
Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg Participants received riociguat 0.5 mg tid (fixed dose).
Placebo Participants received placebo tid.
Total Total of all reporting groups

Baseline Measures
    Riociguat (Adempas, BAY63-2521) up to 2 mg     Riociguat (Adempas, BAY63-2521) up to 1 mg     Riociguat (Adempas, BAY63-2521) Fixed 0.5 mg     Placebo     Total  
Number of Participants  
[units: participants]
  67     33     32     69     201  
Age  
[units: Years]
Mean ± Standard Deviation
  59.3  ± 10.8     55.1  ± 13.2     57.2  ± 9.9     58.9  ± 11.2     58.1  ± 11.2  
Gender  
[units: Participants]
         
Female     12     3     6     8     29  
Male     55     30     26     61     172  
Body mass index  
[units: kg/m^2]
Mean ± Standard Deviation
  28.87  ± 5.27     28.16  ± 4.72     29.20  ± 5.64     28.65  ± 5.89     28.73  ± 5.44  
6-minute walking distance [1]
[units: Meters]
Mean ± Standard Deviation
  380.9  ± 125.80     401.9  ± 101.75     416.6  ± 95.77     382.1  ± 123.51     390.5  ± 116.94  
Left ventricular ejection fraction (LVEF) [2]
[units: Percentage]
Mean ± Standard Deviation
  28.4  ± 5.72     28.8  ± 4.54     27.0  ± 5.21     27.1  ± 5.02     27.8  ± 5.24  
Etiology  
[units: Participants]
         
Ischemic cardiomyopathy     30     12     14     34     90  
Non-ischemic cardiomyopathy     37     20     17     34     108  
Data missing     0     1     1     1     3  
WHO (World Health Organization) functional class [3]
[units: Participants]
         
II     35     20     23     42     120  
III     31     13     9     23     76  
IV     1     0     0     4     5  
Number of participants with diabetes mellitus (including subtypes)  
[units: Participants]
  30     10     13     34     87  
Glomerular filtration rate (GFR)  
[units: mL/min/1.73m^2]
Mean ± Standard Deviation
  65.1  ± 19.10     72.6  ± 22.70     72.0  ± 17.90     68.7  ± 19.90     68.7  ± 19.91  
Number of participants with atrial fibrillation  
[units: Participants]
  9     3     3     9     24  
Number of participants with atrial flutter  
[units: Participants]
  0     0     1     1     2  
Number of participants with pacemaker rhythm  
[units: Participants]
  17     9     7     17     50  
Baseline drug and device therapy [4]
[units: Participants]
         
Cardiac devices     38     17     21     44     120  
Angiotensin-converting enzyme inhibitors     50     25     21     46     142  
Angiotensin II receptor blockers     20     8     10     19     57  
Aldosterone antagonists     51     26     23     53     153  
Beta-blockers     31     16     21     32     100  
Beta-blockers with alpha-blocking activity     30     15     11     30     86  
Loop diuretics     62     31     29     68     190  
Thiazide diuretics     12     3     7     10     32  
Cardiac glycosides     28     12     6     28     74  
Oral anticoagulants     38     16     15     33     102  
Amiodarone     9     3     4     8     24  
[1] 6MWD is a measure for the evaluation of functional exercise capacity.
[2] LVEF is a calculated echocardiography parameter.
[3] 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 pulmonary arterial hypertension (PAH).
[4] A single patient could have more than one drug and device therapy.



  Outcome Measures
  Show All Outcome Measures

1.  Primary:   Pulmonary Artery Mean Pressure (PAPmean) at Rest - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

2.  Secondary:   Venous Oxygen Saturation (SvO2) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

3.  Secondary:   Pulmonary Vascular Resistance (PVR) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

4.  Secondary:   Pulmonary Vascular Resistance Index (PVRi) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

5.  Secondary:   Systemic Vascular Resistance (SVR) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

6.  Secondary:   Systemic Vascular Resistance Index (SVRi) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

7.  Secondary:   Transpulmonary Pressure Gradient (TPG) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

8.  Secondary:   Pulmonary Capillary Wedge Pressure (PCWP) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

9.  Secondary:   Tricuspid Annular Plane Systolic Excursion (TAPSE) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

10.  Secondary:   Systolic Pulmonary Arterial Pressure (PAPsyst) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

11.  Secondary:   Left Ventricular Ejection Fraction (LVEF) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

12.  Secondary:   Left Ventricular End-systolic Volume (LVESV) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

13.  Secondary:   Left Ventricular End-diastolic Volume (LVEDV) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

14.  Secondary:   E-wave Deceleration Time - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

15.  Secondary:   Ratio of Mitral Peak Velocity of Early Filling to Mitral Peak Velocity of Late Filling (E/A) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

16.  Secondary:   6-minute Walking Distance (6MWD) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

17.  Secondary:   WHO (World Health Organization) Functional Class - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

18.  Secondary:   Percentage of Participants With Clinical Worsening   [ Time Frame: At visit 6 (16 weeks) ]

19.  Secondary:   Borg CR 10 Scale - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

20.  Secondary:   EQ-5D Utility Score - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

21.  Secondary:   Minnesota Living With Heart Failure Questionnaire (MLHF) Score - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

22.  Secondary:   Cystatin C - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

23.  Secondary:   N-terminal Pro-brain Natriuretic Peptide (NT-pro BNP) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

24.  Secondary:   Troponin T - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

25.  Secondary:   Asymmetric Dimethylarginine (ADMA) - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]

26.  Secondary:   Osteopontin - Change From Baseline to Week 16   [ Time Frame: Baseline and visit 6 (16 weeks) ]


  Serious Adverse Events


  Other Adverse Events


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Limitations and Caveats
Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Subjects had advanced disease and were heavily pretreated. Baseline values were not comparable between treatment groups.  


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: Bayer
e-mail: clinical-trials-contact@bayerhealthcare.com


Publications of Results:

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT01065454     History of Changes
Other Study ID Numbers: 14308, 2009-015878-35
Study First Received: February 8, 2010
Results First Received: November 6, 2013
Last Updated: January 25, 2014
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Federal Office for Safety in Health Care
Canada: Health Canada
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Japan: Pharmaceuticals and Medical Devices Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Denmark: Danish Medicines Agency
Belgium: The Federal Public Service (FPS) Health, Food Chain Safety and Environment
Singapore: Health Sciences Authority
United States: Food and Drug Administration