Evaluation of the Pharmacodynamic Effect of the Combination of Sildenafil and Riociguat on Blood Pressure and Other Safety Parameters.

NCT01179334 | Completed Phase 2 Results

• 2 other identifiers: 150962010-018863-40
• Study Type: interventional
• Target: 18
• Locations: 9 countries
• Sites: 25

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.

Conditions

Pulmonary Hypertension

Keywords

Pulmonary Hypertension; Riociguat; Blood Pressure

Outcome Measures

Primary Outcomes (1)

• 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.

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Secondary Outcomes (11)

• Maximum Change From Baseline in Standing Systolic Blood Pressure (SBP) Within 4 Hours Post-dose at Visit 6 (Week 12)

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

• Maximum Change From Baseline in Supine Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12)

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

• Maximum Change From Baseline in Standing Diastolic Blood Pressure (DBP) Within 4 Hours Post-dose at Visit 6 (Week 12)

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

• Maximum Change From Baseline in Supine Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12)

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

• Maximum Change From Baseline in Standing Heart Rate (HR) Within 4 Hours Post-dose at Visit 6 (Week 12)

  Pre-dose (baseline) and within 4 hours post-dose at visit 6 (week 12)

Study Arms (2)

Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT

EXPERIMENTAL

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.

Drug: Riociguat (Adempas, BAY63-2521); Drug: Sildenafil

Placebo

PLACEBO COMPARATOR

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.

Drug: Placebo; Drug: Sildenafil

Interventions

Riociguat (Adempas, BAY63-2521) DRUG

BAY63-2521: 1 mg tid - 2,5 mg tid oral for 12 weeks.

Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT

Placebo DRUG

Placebo for 12 weeks

Placebo

Sildenafil DRUG

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

Placebo; Riociguat (Adempas, BAY63-2521) up to 2.5 mg_IDT

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Bayer: lead

Study Sites (25)

Unknown Facility

Aurora, Colorado, 80045, United States

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Columbus, Ohio, 43221, United States

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Providence, Rhode Island, 02903, United States

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Innsbruck, 6020, Austria

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Villach, 9500, Austria

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Vseobecna fakultni nemocnice

Prague, 12808, Czechia

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Heidelberg, Baden-Wurttemberg, 69126, Germany

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Regensburg, Bavaria, 93042, Germany

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Würzburg, Bavaria, 97074, Germany

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Hamburg, Hamburg, 20246, Germany

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Giessen, Hesse, 35392, Germany

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Hanover, Lower Saxony, 30625, Germany

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Cologne, North Rhine-Westphalia, 50924, Germany

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Mönchengladbach, North Rhine-Westphalia, 41063, Germany

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Dresden, Saxony, 01307, Germany

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Berlin, State of Berlin, 13353, Germany

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Bologna, Emilia-Romagna, 40138, Italy

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Pavia, Lombardy, 27100, Italy

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Auckland, 1051, New Zealand

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Christchurch, 8011, New Zealand

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Unknown Facility

Otwock, 05-400, Poland

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Warsaw, 01-138, Poland

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Barcelona, Barcelona, 08036, Spain

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Papworth Hospital

Cambridge, Cambridgeshire, CB23 3RE, United Kingdom

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Unknown Facility

Clydebank, West Dunbartonshire, G81 4DY, United Kingdom

Location

Related Publications (1)

• 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.

  PMID: 25657022 RESULT

MeSH Terms

Conditions

Hypertension, Pulmonary

Interventions

riociguat; Sildenafil Citrate

Condition Hierarchy (Ancestors)

Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer

clinical-trials-contact@bayerhealthcare.com

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2010
• First Posted: August 11, 2010
• Study Start: August 1, 2010
• Primary Completion: June 1, 2012
• Study Completion: May 1, 2013
• Last Updated: August 29, 2016
• Results First Posted: December 25, 2013

Record last verified: 2016-07

Locations

AU (2); GB (2); CZ (1); DE (10); PL (2); US (3); ES (1); IT (2); NZ (2)