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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01179334




Registration number
NCT01179334
Ethics application status
Date submitted
10/08/2010
Date registered
11/08/2010
Date last updated
29/08/2016

Titles & IDs
Public title
Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters.
Scientific title
An Interaction Study to Evaluate Changes in Blood Pressure Following 1, 1.5, 2, and 2.5 mg Riociguat Tid (Dose Titration) Compared to Placebo Treatment on the Background of Stable Sildenafil Pretreatment in Subjects With Symptomatic Pulmonary Arterial Hypertension
Secondary ID [1] 0 0
2010-018863-40
Secondary ID [2] 0 0
15096
Universal Trial Number (UTN)
Trial acronym
PATENT PLUS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Hypertension 0 0
Condition category
Condition code
Cardiovascular 0 0 0 0
Hypertension
Respiratory 0 0 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Riociguat (Adempas, BAY63-2521)
Treatment: Drugs - Placebo
Treatment: Drugs - Sildenafil

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. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.

Placebo Comparator: Placebo - Participants received Placebo orally as a film-coated tablet three times daily (tid) for 12 weeks. Participants continued to take daily stable sildenafil background treatment according to their prescriptions.


Treatment: Drugs: Riociguat (Adempas, BAY63-2521)
BAY63-2521: 1 mg tid - 2,5 mg tid oral for 12 weeks.

Treatment: Drugs: Placebo
Placebo for 12 weeks

Treatment: Drugs: Sildenafil
Participants continued to take daily stable sildenafil background treatment according to their prescriptions.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Maximum Change From Baseline in Supine Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12) - Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.
Timepoint [1] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [1] 0 0
Maximum Change From Baseline in Standing Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12) - Systolic blood pressure (SBP) was measured as standard vital sign parameter. Range allowed in this study: <= 180 mmHg. In addition, SBP must be >=95 mmHg in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent SBP measurements in that profile) within 4 hours post-dose. Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.
Timepoint [1] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [2] 0 0
Maximum Change From Baseline in Supine Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12) - Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.
Timepoint [2] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [3] 0 0
Maximum Change From Baseline in Standing Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12) - Diastolic blood pressure (DBP) was measured as standard vital sign parameter. Range allowed in this study: <= 110 mmHg. The maximum change from baseline at each visit was defined as the within-subject maximum decrease from baseline (or zero if baseline was lower than all subsequent DBP measurements in that profile) within 4 hours post-dose. Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.
Timepoint [3] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [4] 0 0
Maximum Change From Baseline in Supine Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12) - Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug.
Timepoint [4] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [5] 0 0
Maximum Change From Baseline in Standing Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12) - Heart rate (HR) was measured as standard vital sign parameter. Range allowed in this study: <= 105 beats per minute (bpm) in the first 2 hours after intake of background treatment with sildenafil. The maximum change from baseline at each visit was defined as the within-subject maximum increase from baseline (or zero if baseline was higher than all subsequent HR measurements in that profile) within 4 hours post-dose. Baseline was the last HR recorded at and within 30 minutes before intake of study drug.
Timepoint [5] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [6] 0 0
Area Under Effect Curve (AUEC) of Supine SBP Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under the effect curve (AUEC) at each visit of supine SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.
Timepoint [6] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [7] 0 0
Area Under Effect Curve (AUEC) of Standing SBP Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under effect curve (AUEC) at each visit of standing SBP describes an average within-subject change in SBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last SBP recorded at and within 30 minutes before intake of study drug.
Timepoint [7] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [8] 0 0
Area Under Effect Curve (AUEC) of Supine DBP Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under effect curve (AUEC) at each visit of supine DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.
Timepoint [8] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [9] 0 0
Area Under Effect Curve (AUEC) of Standing DBP Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under effect curve (AUEC) at each visit of standing DBP describes an average within-subject change in DBP from baseline over a time-period of 4 hours post-dose (Note that the area only takes values below the individual baseline for the respective visit into account. The area that would result from an increase from baseline is not taken into account for the calculation of the area). Baseline was the last DBP recorded at and within 30 minutes before intake of study drug.
Timepoint [9] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [10] 0 0
Area Under Effect Curve (AUEC) of Supine HR Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under effect curve (AUEC) at each visit of supine HR describes an average within-subject change in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug.
Timepoint [10] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)
Secondary outcome [11] 0 0
Area Under Effect Curve (AUEC) of Standing HR Within 4 Hours Post-dose at Visit 6 (Week 12) - The area under effect curve (AUEC) at each visit of standing HR describes an average within-subject increase in HR from baseline over a time-period of 4 hours post-dose (Note that the area only takes values above the individual baseline for the respective visit into account. The area that would result from a decrease from baseline is not taken into account for the calculation of the area). Baseline was the last HR recorded at and within 30 minutes before intake of study drug.
Timepoint [11] 0 0
Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Eligibility
Key inclusion criteria
- 18 to 75 years of age at Visit 1

- Male and female subjects with symptomatic PAH (Group I Dana Point Updated Clinical
Classification 2008), a 6-min walking distance (6MWD) of more than 150 m, a pulmonary
vascular resistance (PVR) >300 dyn*s*cm-5, and a mean pulmonary artery pressure
(PAPmean) = 25 mmHg

- For Study Part 1: subjects on stable pretreatment with sildenafil at a dose of 20 mg
tid

- Unspecific treatments which may also be used for the treatment of PAH such as oral
anticoagulants, diuretics, digitalis, calcium channel blockers or oxygen
supplementation are permitted. However, treatment with anticoagulants (if indicated)
must have been started at least 30 days before Visit 1 and treatment with diuretics
needs to be stable for at least 30 days before Visit 1

- Subjects with supplemental long-term oxygen therapy may be included, if the amount of
supplemental oxygen and the delivery method was stable on average for at least 90 days
before Visit 1

- SBP >/=95 mmHg and heart rate (HR) </=105 beats per minute (BPM) in the first 2 h
after intake of sildenafil (measured at Visits 0 and 1)

- Women without child-bearing potential

- Subjects who are able to understand and follow instructions and who are able to
participate in the study for the entire period

- Subjects must have given their written informed consent to participate in the study
after having received adequate previous information and prior to any study-specific
procedures
Minimum age
18 Years
Maximum age
75 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Subject's participating in another clinical trial or who have done so within 30 days
before Visit 1

- Previous assignment to treatment during this study

- Pregnant women

- Subjects with a medical disorder, condition, or history of such that would impair the
subject's ability to participate or complete this study in the opinion of the
investigator

- Subjects with substance abuse (eg alcohol or drug abuse) within the previous 180 days
before Visit 1

- Subjects with underlying medical disorders with an anticipated life expectancy below 2
years (eg active cancer disease with localized and/or metastasized tumor mass)

- Subjects with a history of severe allergies or multiple drug allergies

- Subjects with hypersensitivity to the investigational drug or any of the excipients

- Subjects unable to perform a valid 6MWD test, eg subjects with a severe peripheral
artery occlusive disease

- Subjects with a relative difference (ie absolute difference/mean) of more than 15%
between the eligibility- and the baseline 6MWD test

- All types of pulmonary hypertension except subtypes of Updated Clinical Classification
of pulmonary hypertension (PH) (Dana Point 2008) Group I specified in the inclusion
criteria

- Moderate to severe obstructive lung disease (forced expiratory volume <60% predicted).
The predicted forced expiratory volume in 1 second (FEV1) is a calculated value

- Severe restrictive lung disease (total lung capacity <70% predicted). The predicted
total lung capacity (TLC) is a calculated value

- Severe congenital abnormalities of the lungs, thorax, and diaphragm

- Oxygen saturation (SaO2) <88% despite supplemental oxygen therapy

- Arterial partial oxygen pressure (PaO2) <55 mmHg despite supplemental oxygen therapy

- Arterial partial pressure of carbon dioxide (PaCO2) >45 mmHg

- Uncontrolled arterial hypertension (SBP >180 mmHg and /or diastolic blood pressure
>110 mmHg

- Atrial fibrillation within the last 90 days before Visit 1

- Pulmonary venous hypertension with pulmonary capillary wedge pressure 15 mmHg

- Hypertrophic obstructive cardiomyopathy

- Severe proven or suspected coronary artery disease

- Clinical evidence of symptomatic atherosclerotic disease

- Congenital or acquired valvular or myocardial disease if clinically significant apart
from tricuspid valvular insufficiency due to pulmonary hypertension

- Clinical relevant hepatic dysfunction indicated by:

- Bilirubin >2 times upper limit normal (ULN)

- and/or ALT (alanine aminotransferase) or AST (aspartate aminotransferase) >3
times ULN

- and/or signs of severe hepatic insufficiency (eg impaired albumin synthesis with
an albumin <32 g/L, hepatic encephalopathy > grade 1

- Renal insufficiency (glomerular filtration rate <30 mL/min, eg calculated based on the
Cockcroft-Gault or Modification of Diet in Renal Disease (MDRD) formulas

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
Ohio
Country [3] 0 0
United States of America
State/province [3] 0 0
Rhode Island
Country [4] 0 0
Austria
State/province [4] 0 0
Innsbruck
Country [5] 0 0
Austria
State/province [5] 0 0
Villach
Country [6] 0 0
Czech Republic
State/province [6] 0 0
Praha 2
Country [7] 0 0
Germany
State/province [7] 0 0
Baden-Württemberg
Country [8] 0 0
Germany
State/province [8] 0 0
Bayern
Country [9] 0 0
Germany
State/province [9] 0 0
Hessen
Country [10] 0 0
Germany
State/province [10] 0 0
Niedersachsen
Country [11] 0 0
Germany
State/province [11] 0 0
Nordrhein-Westfalen
Country [12] 0 0
Germany
State/province [12] 0 0
Sachsen
Country [13] 0 0
Germany
State/province [13] 0 0
Berlin
Country [14] 0 0
Germany
State/province [14] 0 0
Hamburg
Country [15] 0 0
Italy
State/province [15] 0 0
Emilia-Romagna
Country [16] 0 0
Italy
State/province [16] 0 0
Lombardia
Country [17] 0 0
New Zealand
State/province [17] 0 0
Auckland
Country [18] 0 0
New Zealand
State/province [18] 0 0
Christchurch
Country [19] 0 0
Poland
State/province [19] 0 0
Otwock
Country [20] 0 0
Poland
State/province [20] 0 0
Warszawa
Country [21] 0 0
Spain
State/province [21] 0 0
Barcelona
Country [22] 0 0
United Kingdom
State/province [22] 0 0
Cambridgeshire
Country [23] 0 0
United Kingdom
State/province [23] 0 0
West Dunbartonshire

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Bayer
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Pulmonary Arterial Hypertension (PAH) is a severe progressive disease with a high mortality.
Although several drugs are available for the treatment of PAH none offer a cure, therefore
there is still a high medical need for new treatments.

Soluble guanylate cyclase (sGC) is one of the chemicals involved in the pathways controlling
vascular tone, which is impaired in patients with PAH. This causes constriction and
thickening of the blood vessels wall in the lungs and increase of blood pressure in the
lungs. This can lead to the very debilitating symptoms of PAH such as tiredness, shortness of
breath on exertion, collapse and often the inability of the patient to perform their daily
life activities.

Inhalation of Nitric Oxide, which activates sGC is used to treat PAH, but its effect wears
off as soon as inhalation stops. Direct stimulation of sGC using this new compound Riociguat
may be a new approach for the treatment of PAH.

The phosphodiesterase 5 (PDE5)-inhibitor Sildenafil is one of licensed treatments for PAH.
The Patent Plus is a double-blind, placebo-controlled safety study, designed to investigate
the effect of Riociguat on blood pressure in patients with PAH when given in combination with
Sildenafil.
Trial website
https://clinicaltrials.gov/show/NCT01179334
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Bayer Study Director
Address 0 0
Bayer
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications