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

Pulmonary Disease, Chronic Obstructive Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00640315
• Other study ID #: 12915
• Secondary ID: 2007-003919-31
• Status: Completed
• Phase: Phase 2
• First received: February 29, 2008
• Last updated: January 27, 2014
• Start date: August 2008
• Est. completion date: September 2009

Study information

• Verified date: January 2014
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial Summary

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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 23
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Disease
• Hypertension
• Hypertension, Pulmonary
• Lung Diseases
• Lung Diseases, Obstructive
• Pulmonary Disease, Chronic Obstructive

Intervention

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).
• 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).

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Bayer

Country where clinical trial is conducted

Germany, 

References & Publications (1)

H.-A. Ghofrani, G. Staehler, E. Gruenig, M. Halank, V. Mitrovic, S. Unger, W. Mueck, R. Frey, J. Behr. The Effect Of The Soluble Guanylate Cyclase Stimulator Riociguat On Hemodynamics In Patients With Pulmonary Hypertension Due To Chronic Obstructive Pulm

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mean PR Duration (PRmean) - Change From Baseline to Day 3	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.	Baseline and day 3	Yes
Other	Mean QRS Duration (QRSmean) - Change From Baseline to Day 3	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.	Baseline and day 3	Yes
Other	Mean QT Duration (QTmean) - Change From Baseline to Day 3	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.	Baseline and day 3	Yes
Other	Mean QTcB Duration (Bazett's Correction Formula, QTcB) - Change From Baseline to Day 3	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.	Baseline and day 3	Yes
Other	Mean QTcF Duration (Fridericia's Correction Formula, QTcF) - Change From Baseline to Day 3	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.	Baseline and day 3	Yes
Primary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Pulmonary Artery Pressure (PAPmean)	PAPmean was reported during right heart catheterization	From baseline up to 4 hours after administration	No
Primary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Vascular Resistance (PVR)	PVR was calculated according to the formula PVR = 80*(PAPmean - pulmonary capillary wedge pressure)/cardiac output	From baseline up to 4 hours after administration	No
Primary	Area Under the Plasma Concentration Versus Time Curve From Zero to Infinity (AUC) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Primary	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		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	No
Primary	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		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	No
Primary	Maximum Drug Concentration in Plasma (Cmax) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Primary	Maximum Drug Concentration in Plasma Divided by Dose (Cmax/D) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Primary	Maximum Drug Concentration in Plasma Divided by Dose Per kg Body Weight (Cmax,Norm) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Right Atrial Pressure (RAPmean)	RAPmean was reported during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systolic Pulmonary Artery Pressure (PAPsyst)	PAPsyst was acquired during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Diastolic Pulmonary Artery Pressure (PAPdiast)	PAPdiast was acquired during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Capillary Wedge Pressure (PCWP)	PCWP was acquired during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Heart Rate (HR)	HR was acquired during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systolic Blood Pressure (SBP)	Systolic arterial blood pressure was acquired during right heart catheterization.	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Diastolic Blood Pressure (DBP)	Diastolic arterial blood pressure was acquired during right heart catheterization.	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Mean Arterial Pressure (MAP)	MAP was acquired during right heart catheterization	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Cardiac Output (CO)	CO was measured in triplicate by the thermodilution technique	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Pulmonary Vascular Resistance Index (PVRI)	PVRI was calculated as PVRI = (80*(PAPmean - PCWP)/CO)*body surface area	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systemic Vascular Resistance (SVR)	SVR was calculated as SVR = 80*(MAP-RAPmean)/CO	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Systemic Vascular Resistance Index (SVRI)	SVRI was calculated as SVRI = (80*(MAP - RAPmean)/CO)*body surface area	From baseline up to 4 hours after administration	No
Secondary	Swan-Ganz Hemodynamics - Maximal Change From Baseline at Day 1 of Cardiac Index	Cardiac index was calculated as cardiac index = CO / body surface area.	From baseline up to 4 hours after administration	No
Secondary	Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Partial Oxygen Pressure (PaO2)	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".	Baseline and 2 hours post dose	No
Secondary	Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Partial Pressure of Carbon Dioxide (PaCO2)	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".	Baseline and 2 hours post dose	No
Secondary	Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Venous Oxygen Pressure (PvO2)	Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".	Baseline and 2 hours post dose	No
Secondary	Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Arterial Oxygen Saturation (SaO2)	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".	Baseline and 2 hours post dose	No
Secondary	Blood Gas Analysis - Percentage Change From Baseline at 2 Hours Post Dose of Venous Oxygen Saturation (SvO2)	Percent change was calculated as "100%*(value post dose - value at baseline)/ value at baseline".	Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Forced Expiratory Volume in 1 Second (FEV1)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted FEV1		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Forced Vital Capacity (FVC)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted FVC		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of FEV1/FVC		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Total Lung Capacity (TLC)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted TLC	The percent of predicted TLC was provided by investigator at site.	Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Residual Volume (RV)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted RV		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 75% of Expiratory Vital Capacity (MEF75)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 50% of Expiratory Vital Capacity (MEF50)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Maximal Expiratory Flow at 25% of Expiratory Vital Capacity (MEF25)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Total Airway Resistance (Raw)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Vital Capacity (VC)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Percent of Predicted VC		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Diffusing Capacity of the Lung for Carbon Monoxide (DLCO)		Baseline and 2 hours post dose	No
Secondary	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)		Baseline and 2 hours post dose	No
Secondary	Lung Function - Percentage Change From Baseline at 2 Hours Post Dose of Specific Diffusing Capacity		Baseline and 2 hours post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Total Ventilation (V)		Baseline and 1 hour post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Total Perfusion (Q)		Baseline and 1 hour post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Dead Space Ventilation		Baseline and 1 hour post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Low V/Q Perfusion		Baseline and 1 hour post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Normal V/Q Perfusion		Baseline and 1 hour post dose	No
Secondary	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		Baseline and 1 hour post dose	No
Secondary	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		Baseline and 1 hour post dose	No
Secondary	Multiple Inert Gas Elimination Technique (MIGET) Analysis - Change From Baseline at 1 Hour Post Dose of Intrapulmonary Shunt Flow		Baseline and 1 hour post dose	No
Secondary	Time to Reach Maximum Drug Concentration in Plasma (Tmax) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Secondary	Half-life Associated With the Terminal Slope (t1/2) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Secondary	Mean Residence Time (MRT) of Riociguat and Metabolite M1 After Single Dose of Riociguat		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	No
Secondary	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		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	No

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