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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/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
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Cardiovascular 0 0 0 0
Hypertension

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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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
Sex
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
1/08/2010
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
1/05/2013
Sample size
Target
Accrual to date
Final
18
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/study/NCT01179334
Trial related presentations / publications
Galie N, Muller K, Scalise AV, Grunig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J. 2015 May;45(5):1314-22. doi: 10.1183/09031936.00105914. Epub 2015 Feb 5.
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

For IPD and results data, please see https://clinicaltrials.gov/study/NCT01179334