A Research Study To Assess The Effectiveness And Safety Of Different Doses Of Oral PF-00489791 In The Treatment Of Adult Patients With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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Study will assess PF-00489791 efficacy and safety in Pulmonary Arterial Hypertension (PAH)

Detailed Description
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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.

Official Title
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A Phase 2a, Randomized, Double Blind, Placebo-controlled, Parallel Group Study Investigating The Dose-response Of Pf-00489791 On Acute Hemodynamics In Subjects With Idiopathic And Familial Pulmonary Arterial Hypertension

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: PF-00489791
* Drug: placebo
* Drug: sildenafil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Idiopathic or familial pulmonary arterial hypertension (PAH) Mean PAP at least 25 mm Hg, PCWP < 15 mm Hg at rest For females of child-bearing potential negative pregnancy test at screening and use of contraception during the study and 4 weeks after its completion Signed and dated informed consent Willingness to comply with the study plan and procedures Exclusion Criteria: pulmonary arterial hypertension (PAH)other than idiopathic or familial For females, pregnancy or lactation Use of specific PAH treatments, potent CYP3A4 inhibitors, protease inhibitors, alpha blockers or arginine 30 days prior tio randomization and during the study Change of dose or class of standard background PAH therapy, i.e. oxygen, calcium channel blockers, digoxin, diuretics 30 days prior tio randomization and during the study Large shift in altitude (defined as >5000 feet or 1524 meters) during 90 days prior to baseline visit and/or during the study visit Subjects with intracardiac shunts and/or serious heart, lung or other health conditions HIV positive subjects Subjects participating in another clinical trial with an investigational drug or device Subjects with degenerative retinal disorders, history of non-arteritic anterior ischemic optic neuropathy or untreated proliferative diabetic retinopathy Allergies and previous intolerance of PDE5 inhibitors Alcohol or drug abuse Blood donation during the study, or 1 month before or after the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-00489791 1 mg<br> | Drug: PF-00489791<br>* tablet form, 1 mg, single dose (Day 1)<br>|
| Experimental: PF-00489791 2 mg<br> | Drug: PF-00489791<br>* tablet form, 2 mg, single dose (Day 1)<br>|
| Experimental: PF-00489791 4 mg<br> | Drug: PF-00489791<br>* tablet form, 4 mg, single dose (Day 1)<br>|
| Experimental: PF-00489791 10 mg<br> | Drug: PF-00489791<br>* tablet form, 10 mg, single dose (Day 1)<br>|
| Experimental: PF-00489791 20 mg<br> | Drug: PF-00489791<br>* tablet form, 20 mg, single dose (Day 1)<br>|
| Placebo Comparator: Placebo<br> | Drug: placebo<br>* tablet form, single dose (Day 1)<br>|
| Active Comparator: Sildenafil<br>Observational comparator arm | Drug: sildenafil<br>* tablet form, 20 mg, single dose (Day 1)<br>* Other names: Revatio;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, up to 4 hours post-dose on Day 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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). | 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. | 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). | 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. | 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. | Baseline; 1, 4 hours post-dose on Day 1 | 
| Plasma Concentration of PF-00489791 and Sildenafil |  | 1, 2, 3, 4, 5, 6, 8 hours post-dose on Day 1, follow up (Day 3 to 5) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH pulmonary hypertension pulmonary arterial hypertension