Study will assess PF-00489791 efficacy and safety in Pulmonary Arterial Hypertension (PAH)
Pfizer decided to stop this trial early upon Stage 1 completion due to change in PF-00489791 development and not as a result of safety concerns for PF-00489791. Date of termination (LSLV) occurred on July 28, 2010.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
48
tablet form, 1 mg, single dose (Day 1)
tablet form, 2 mg, single dose (Day 1)
tablet form, 4 mg, single dose (Day 1)
Mean Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) Over 4 Hours Post Dose
PVRI was calculated as: PVRI (in Wood units\*meter\^2 \[m\^2\]) = pulmonary vascular resistance (PVR) multiplied by body surface area (BSA). PVR (in Wood units) = (mean pulmonary artery pressure \[mean PAP\] minus pulmonary capillary wedge pressure \[PCWP\]) divided by cardiac output (CO, taken as the average of the triplicate measurements). BSA (m\^2) = (0.007184) multiplied by (height in centimeters \[cm\])\^0.725 multiplied by (weight in kilograms \[kg\])\^0.425. PVRI values were converted to dyne\*second (s)\*m\^2/centimeter (cm)\^5 from Woods units by multiplying by a factor of 79.9. The change from baseline in PVRI over 4-hour interval was calculated as the average of the change from baseline values at 1, 2, 3, and 4 hours post dose on Day 1.
Time frame: Baseline, up to 4 hours post-dose on Day 1
Greatest Reduction From Baseline in Pulmonary Vascular Resistance Index (PVRI) and Systemic Vascular Resistance Index (SVRI) Over 4 Hours Post Dose
PVRI was calculated as: PVRI (in Wood units\*m\^2) = PVR multiplied by BSA. PVR (in Wood units) = (mean PAP minus PCWP) divided by CO (taken as the average of the triplicate measurements). SVRI was calculated as: SVRI (Wood units\*m\^2) = systemic vascular resistance (SVR) multiplied by BSA. SVR (Wood units) = (mean systemic arterial pressure \[mean SAP\] minus right atrial pressure \[RAP\]) divided by CO (taken as the average of the triplicate measurements). BSA (m\^2) = (0.007184) multiplied by (height in cm)\^0.725 multiplied by (weight in kg)\^0.425. PVRI and SVRI values were converted to dyne\*s\*m\^2/cm\^5 from Woods units by multiplying by a factor of 79.9. For each participant the greatest reduction (GR) from baseline in PVRI and SVRI over 4-hour interval was defined as the maximum reduction (greatest decrease or smallest increase) observed at 1, 2, 3, and 4 hours post dose on Day 1.
Time frame: Baseline, up to 4 hours post-dose on Day 1
Mean Change From Baseline in Systemic Vascular Resistance Index (SVRI) Over 4 Hours Post Dose
SVRI was calculated as: SVRI (Wood units\*m\^2) = SVR multiplied by BSA. SVR (Wood units) = (mean SAP minus RAP) divided by CO (taken as the average of the triplicate measurements). BSA (m\^2) = (0.007184) multiplied by (height in cm)\^0.725 multiplied by (weight in kg)\^0.425. SVRI values were converted to dyne\*s\*m\^2/cm\^5 from Woods units by multiplying by a factor of 79.9. The change from baseline in SVRI over 4-hour interval was calculated as the average of the change from baseline values at 1, 2, 3, and 4 hours post dose on Day 1.
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tablet form, 10 mg, single dose (Day 1)
tablet form, 20 mg, single dose (Day 1)
tablet form, single dose (Day 1)
tablet form, 20 mg, single dose (Day 1)
Pulmonary Associates, PA
Phoenix, Arizona, United States
John C. Lincoln Hospital, North Mountain
Phoenix, Arizona, United States
Pulmonary Associates, PA
Phoenix, Arizona, United States
Shands at University of Florida
Gainesville, Florida, United States
Creighton University Medical Center
Omaha, Nebraska, United States
Allegheny General Hospital
Pittsburgh, Pennsylvania, United States
UT Southwestern Medical Center - Department of Internal Medicine Pulmonary
Dallas, Texas, United States
UT Southwestern St. Paul Hospital
Dallas, Texas, United States
Lawson Health Research Institute
London, Ontario, Canada
London Health Sciences Centre
London, Ontario, Canada
...and 15 more locations
Time frame: Baseline, up to 4 hours post-dose on Day 1
Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Hour 1, 2, 3 and 4 Post Dose
PVRI was calculated as: PVR multiplied by BSA. PVR = (mean PAP minus PCWP) divided by CO (taken as the average of the triplicate measurements). BSA (m\^2) = 0.007184 times height (cm)\^0.725 times weight (kilogram)\^0.425. Wood unit equals to 79.9 dyne\*second/cm\^5. Hourly changes from baseline in PVRI was reported.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Change From Baseline in Systemic Vascular Resistance Index (SVRI) at Hour 1, 2, 3 and 4 Post Dose
SVRI is the product of SVR and BSA. SVR equals to (mean SAP subtracted by RAP) divided by CO (taken as the average of the triplicate measurements). BSA (m\^2) equals to 0.007184 times height (cm)\^0.725 times weight (kilogram) \^0.425. Wood unit equals to 79.9 dyne\*second/cm\^5. Hourly changes from baseline in SVRI was reported.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Change From Baseline in Cardiac Index (CI) at Hour 1, 2, 3 and 4 Post Dose
CI was calculated as: CI (liters per minute per square meter \[L/min/m\^2\]) = CO (taken as the average of the triplicate measurements) divided by BSA. BSA (m\^2) = (0.007184) multiplied by (height in cm)\^0.725 multiplied by (weight in kg)\^0.425.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP), Systolic Pulmonary Artery Pressure (sPAP), Diastolic Pulmonary Artery Pressure (dPAP), Right Atrial Pressure (RAP) at Hour 1, 2, 3 and 4 Post Dose
Hourly changes from baseline in hemodynamic parameters were reported. Hemodynamic parameters including mPAP, sPAP, dPAP and RAP were measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position. All hemodynamic pressure measurements were performed as triplicate measurements and average was used.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP), Mean Systemic Arterial Pressure (SAP), Systolic Systemic Arterial Pressure (sSAP) and Diastolic Systemic Arterial Pressure (dSAP) at Hour 1, 2, 3 and 4 Post Dose
Hourly changes from baseline in hemodynamic parameters were reported. Hemodynamic parameters including PCWP, SAP, sSAP and dSAP were measured using a pressure transducer positioned at the mid-axillary line with the participant in the supine position. All hemodynamic pressure measurements (except PCWP for which 1 measurement is sufficient) were performed as triplicate measurements and average was used.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Mean Change From Baseline in Pulmonary Vascular Resistance (PVR) and Systemic Vascular Resistance (SVR) at Hour 1, 2, 3 and 4 Post Dose
Hourly changes from baseline in PVR and SVR were reported. PVR was calculated by: PVR (Wood units) = (mean PAP minus PCWP) divided by CO (taken as the average of the triplicate measurements). SVR (Wood units) = (mean SAP minus RAP) divided by CO (taken as the average of the triplicate measurements).
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Mean Change From Baseline in Heart Rate (HR) at Hour 1, 2, 3 and 4 Post Dose
Hourly changes from baseline in HR were reported.
Time frame: Baseline, 1, 2, 3, 4 hours post-dose on Day 1
Number of Participants With Clinically Significant Laboratory Values
Criteria for clinically significant laboratory values:hemoglobin, hematocrit and red blood cells(less than\[\<\]0.8\*lower limit of normal\[LLN\]); leucocytes (\<0.6\*LLN/greater than\[\>\]1.5\*upper limit of normal\[ULN\]);platelets (\<0.5\*LLN\>\</0\>1.75\* ULN);neutrophils, lymphocytes(\<0.8\*LLN\>\</0\>1.2\* ULN); eosinophils, basophils, monocytes (\>1.2\*ULN);bilirubin (\>1.5\*ULN);aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase(\>3\*ULN);creatinine, blood urea nitrogen (\>1.3\*ULN);glucose(\<0.6\*LLN\>\</0\>1.5\* ULN); uric acid(\>1.2\*ULN);sodium(\<0.95\*LLN\>\</0\>1.05\*ULN); potassium, chloride, calcium(\<0.9\*LLN\>\</0\>1.1\* ULN); albumin, total protein(\<0.8\>\</0\>1.2\* ULN); creatine kinase(\>2.0\*ULN);urine red blood cells(RBCs), urine white blood cells(WBCs)(\>=6 per high-powered field);qualitative urine glucose, urine ketones, urine protein, urine blood/hemoglobin(\>=1); urine bacteria(\>20 per high-powered field); pregnancy test, urine protein, quantitative random serum pregnancy test (\>=1).
Time frame: Baseline up-to follow up (Day 3 to 5)
Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Values
Criteria for clinically significant changes (changes of potential clinical concern) in ECG parameters: increase from baseline of \>=30 to \<60 milliseconds (msec) or \>=60 msec in corrected QT interval (QTc), QT interval corrected using Fridericia's correction (QTcF) and QT interval corrected using Bazett's correction (QTcB); Increase from baseline of \>= 25% (when baseline was \>200 msec) or increase from baseline of \>=50% (when baseline was \<=200 msec) in PR interval; and Increase from baseline of \>= 25% (when baseline was \>100 msec) or increase from baseline of \>=50% (when baseline was \<=100 msec) in QRS interval. Number of participants with any clinically significant change in ECG values were reported.
Time frame: Baseline up-to follow up (Day 3 to 5)
Change From Baseline in Mean Partial Pressure of Oxygen (PaO2) and Carbon Dioxide (PaCO2) at Hour 1 and 4 Post Dose
Arterial blood samples for PaO2 and PaCO2 collected via an arterial line were assessed. PaO2 is the measure of oxygen level in the arterial blood and PaCO2 is the measure of carbon dioxide level in the arterial blood.
Time frame: Baseline; 1, 4 hours post-dose on Day 1
Plasma Concentration of PF-00489791 and Sildenafil
Time frame: 1, 2, 3, 4, 5, 6, 8 hours post-dose on Day 1, follow up (Day 3 to 5)