Single Dose Study in Patients With Chronic Obstructive Pulmonary Disease (COPD) Associated Pulmonary Hypertension.

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00640315
First received: February 29, 2008
Last updated: January 27, 2014
Last verified: January 2014
  Purpose

This study is to demonstrate the safety, tolerability, pharmakokinetic and pharmacodynamic effect of a single oral dose of BAY63-2521 in patients with pulmonary hypertension due to chronic obstructive pulmonary disease (COPD).


Condition Intervention Phase
Hypertension, Pulmonary
Pulmonary Disease, Chronic Obstructive
Drug: Riociguat (Adempas, BAY63-2521) 1.0 mg
Drug: Riociguat (Adempas, BAY63-2521) 2.5 mg
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Proof of Concept Study to Investigate Safety, Tolerability, Pharmacokinetics and the Impact on Pulmonary and Systemic Hemodynamics, Gas Exchange and Lung Function Parameters of a Single-dose of BAY63-2521 IR-tablet in Patients With COPD Associated Pulmonary Hypertension in an Non-randomized, Non-blinded Design

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Pulmonary Artery Pressure (PAPmean) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PAPmean was reported during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Vascular Resistance (PVR) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PVR was calculated according to the formula PVR = 80*(PAPmean - pulmonary capillary wedge pressure)/cardiac output

  • Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUC) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity Divided by Dose (AUC/D) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity Divided by Dose Per kg Body Weight (AUCnorm) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Maximum Drug Concentration in Plasma (Cmax) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Maximum Drug Concentration in Plasma Divided by Dose (Cmax/D) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Right Atrial Pressure (RAPmean) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    RAPmean was reported during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systolic Pulmonary Artery Pressure (PAPsyst) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PAPsyst was acquired during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Diastolic Pulmonary Artery Pressure (PAPdiast) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PAPdiast was acquired during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Capillary Wedge Pressure (PCWP) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PCWP was acquired during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Heart Rate (HR) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    HR was acquired during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systolic Blood Pressure (SBP) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    Systolic arterial blood pressure was acquired during right heart catheterization.

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Diastolic Blood Pressure (DBP) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    Diastolic arterial blood pressure was acquired during right heart catheterization.

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Arterial Pressure (MAP) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    MAP was acquired during right heart catheterization

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Cardiac Output (CO) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    CO was measured in triplicate by the thermodilution technique

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Vascular Resistance Index (PVRI) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    PVRI was calculated as PVRI = (80*(PAPmean - PCWP)/CO)*body surface area

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systemic Vascular Resistance (SVR) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    SVR was calculated as SVR = 80*(MAP-RAPmean)/CO

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systemic Vascular Resistance Index (SVRI) [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    SVRI was calculated as SVRI = (80*(MAP - RAPmean)/CO)*body surface area

  • Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Cardiac Index [ Time Frame: From baseline up to 4 hours after administration ] [ Designated as safety issue: No ]
    Cardiac index was calculated as cardiac index = CO / body surface area.

  • Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Partial Oxygen Pressure (PaO2) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    Arterial blood gas analysis was performed by insertion of an indwelling arterial cannula. Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".

  • Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Partial Pressure of Carbon Dioxide (PaCO2) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    Arterial blood gas analysis was performed by insertion of an indwelling arterial cannula. Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".

  • Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Venous Oxygen Pressure (PvO2) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".

  • Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Oxygen Saturation (SaO2) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    Arterial blood gas analysis was performed by insertion of an indwelling arterial cannula. Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".

  • Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Venous Oxygen Saturation (SvO2) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".

  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Forced Expiratory Volume in 1 Second (FEV1) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted FEV1 [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Forced Vital Capacity (FVC) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted FVC [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of FEV1/FVC [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Total Lung Capacity (TLC) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted TLC [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
    The percent of predicted TLC was provided by investigator at site.

  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Residual Volume (RV) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted RV [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 75% of Expiratory Vital Capacity (MEF75) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 50% of Expiratory Vital Capacity (MEF50) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 25% of Expiratory Vital Capacity (MEF25) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Total Airway Resistance (Raw) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Vital Capacity (VC) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted VC [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Total Lung Capacity at the Time When the DLCO is Measured (Alveolar Volume, VA) [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Specific Diffusing Capacity [ Time Frame: Baseline and 2 hours post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Total Ventilation (V) [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Total Perfusion (Q) [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Dead Space Ventilation [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Low V/Q Perfusion [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Normal V/Q Perfusion [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hours Post Dose of Ventilation-perfusion Distribution Presented as Standard Deviation (SD) of Perfusion [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Ventilation-perfusion Distribution Presented as Standard Deviation (SD) of Ventilation [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Intrapulmonary Shunt Flow [ Time Frame: Baseline and 1 hour post dose ] [ Designated as safety issue: No ]
  • Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Half-life Associated With the Terminal Slope (t1/2) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Mean Residence Time (MRT) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]
  • Area Under the Plasma Concentration Verse Time Curve From Zero to the Last Data Point (AUC0-tn) of Riociguat and Metabolite M1 After Single Dose of Riociguat [ Time Frame: Study day 1: 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, 24, 36 hours post-dose; Study day 3: 0, 2, 6, 12, 24 hours post-dose ] [ Designated as safety issue: No ]

Other Outcome Measures:
  • Mean PR Duration (PRmean) - Change From Baseline to Day 3 [ Time Frame: Baseline and day 3 ] [ Designated as safety issue: Yes ]
    PR duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

  • Mean QRS Duration (QRSmean) - Change From Baseline to Day 3 [ Time Frame: Baseline and day 3 ] [ Designated as safety issue: Yes ]
    QRS duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

  • Mean QT Duration (QTmean) - Change From Baseline to Day 3 [ Time Frame: Baseline and day 3 ] [ Designated as safety issue: Yes ]
    QT duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

  • Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Day 3 [ Time Frame: Baseline and day 3 ] [ Designated as safety issue: Yes ]
    Bazett-corrected QTcB duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.

  • Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Day 3 [ Time Frame: Baseline and day 3 ] [ Designated as safety issue: Yes ]
    Fridericia-corrected QTcF duration was evaluated as part of the 12-lead electrocardiogram. ECGs were recorded after the participant had been at rest for 15 minutes in a supine position.


Enrollment: 23
Study Start Date: August 2008
Study Completion Date: September 2009
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Riociguat (Adempas, BAY63-2521) 1.0 mg
Participants received two single oral doses of 1.0 mg riociguat on study day 1 and study day 3.
Drug: Riociguat (Adempas, BAY63-2521) 1.0 mg
1.0 mg BAY63-2521 will be given twice per subject, as single dose administration during the hemodynamic investigation (on study day 1) and during the lung function testing (on study day 3).
Experimental: Riociguat (Adempas, BAY63-2521) 2.5 mg
Participants received two single oral doses of 2.5 mg riociguat on study day 1 and study day 3.
Drug: Riociguat (Adempas, BAY63-2521) 2.5 mg
2.5 mg BAY63-2521 will be given twice per subject, as single dose administration during the hemodynamic investigation (on study day 1) and during the lung function testing (on study day 3).

Detailed Description:

In addition to the pharmacodynamic and pharmacokinetic variables, the following laboratory variables were assessed:

  • Hematology: Leucocytes, erythrocytes, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelets, white blood cell (WBC), partial thromboplastin time (PTT), prothrombin time (Quick), international normalized ratio (INR) (prothrombin time expressed in relation to normal value) ;
  • Clinical chemistry: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), gamma glutamyl transpeptidase (GGT), creatine phosphokinase (CK), lipase, cholinesterase (CHE), glucose, creatinine, urea, uric acid, bilirubin, total protein, serum albumin, sodium, potassium, calcium, chloride.

And due to the small number of subjects analyzed at several local labs, no summary statistics were provided.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients with pulmonary hypertension due to COPD, undergoing routine invasive measurement of hemodynamic parameters.
  • Catheters for measurement of hemodynamic parameters (PAP [pulmonary artery pressure], PCWP [pulmonary capillary wedge pressure], CO [cardiac output], SBP [systolic blood pressure]) must be in place independent of the trial.

Exclusion Criteria:

  • Acute exacerbation of COPD,
  • Pre-existing lung disease other than COPD,
  • Acute or severe chronic left heart failure,
  • Severe coronary artery disease,
  • Uncontrolled arterial hypertension;
  • Severe left ventricular hypertrophy,
  • Congenital or acquired valvular or myocardial disease,
  • Systolic blood pressure < 100 mmHg,
  • Heart rate < 55 bpm or >105 bpm,
  • PaO2 (arterial partial oxygen pressure)/FiO2 (fraction of inspired oxygen) < 50 mmHg,
  • PaCO2 (arterial partial pressure of carbon dioxide) > 55 mmHg,
  • Severe hepatic insufficiency,
  • Severe renal insufficiency.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00640315

Locations
Germany
Heidelberg, Baden-Württemberg, Germany, 69126
Löwenstein, Baden-Württemberg, Germany, 74245
München, Bayern, Germany, 81377
Bad Nauheim, Hessen, Germany, 61231
Gießen, Hessen, Germany, 35392
Greifswald, Mecklenburg-Vorpommern, Germany, 17475
Dresden, Sachsen, Germany, 01307
Sponsors and Collaborators
Bayer
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
No publications provided

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00640315     History of Changes
Other Study ID Numbers: 12915, 2007-003919-31
Study First Received: February 29, 2008
Results First Received: November 7, 2013
Last Updated: January 27, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Keywords provided by Bayer:
Chronic obstructive pulmonary disease
COPD
Pulmonary hypertension

Additional relevant MeSH terms:
Hypertension, Pulmonary
Chronic Disease
Hypertension
Lung Diseases
Respiration Disorders
Pulmonary Disease, Chronic Obstructive
Lung Diseases, Obstructive
Disease Attributes
Pathologic Processes
Vascular Diseases
Cardiovascular Diseases
Respiratory Tract Diseases

ClinicalTrials.gov processed this record on April 20, 2014