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

Hypertension, Pulmonary Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00853112
• Other study ID #: A7331009
• Secondary ID: 2008-003572-21
• Status: Terminated
• Phase: Phase 2
• First received: February 27, 2009
• Last updated: September 20, 2017
• Start date: April 2009
• Est. completion date: July 2010

Study information

• Verified date: September 2017
• Source: Pfizer
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Description:

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 48
• Est. completion date: July 2010
• Est. primary completion date: July 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Hypertension, Pulmonary

Intervention

Drug:
• PF-00489791
tablet form, 1 mg, single dose (Day 1)
• PF-00489791
tablet form, 2 mg, single dose (Day 1)
• PF-00489791
tablet form, 4 mg, single dose (Day 1)
• PF-00489791
tablet form, 10 mg, single dose (Day 1)
• PF-00489791
tablet form, 20 mg, single dose (Day 1)
• placebo
tablet form, single dose (Day 1)
• sildenafil
tablet form, 20 mg, single dose (Day 1)

Locations

Country	Name	City	State
Canada	Lawson Health Research Institute	London	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Sir Mortimer B. Davis, Jewish General Hospital	Montreal	Quebec
Germany	Thoraxklinik am Universitaetsklinikum	Heidelberg
India	Department Of Cardiology, MediCiti Hospital,	Hyderabad	Andhra Pardesh
India	Omega Hospital	Mangalore	Karnataka
India	Department Of Cardiology, Sri Venkateswara Institute Of Medical Sciences	Tirupati	Andhra Pardesh
India	Bankers Heart Institute	Vadodara	Gujarat
Russian Federation	Institute of Cardiosurgery n.a. V.I.Burakovsky	Moscow
Russian Federation	Moscow Healthcare Institution "City Clinical Hospital No. 57"	Moscow
Spain	Hospital Clinic I Provincial	Barcelona
Spain	Hospital General Universitari Vall D´Hebron	Barcelona
Spain	Hospital Universitario 12 de Octubre	Madrid
Sweden	Universitetssjukhuset i Lund, Hjart- och Lungdivisionen	Lund
Sweden	Norrlands Universitetssjukhus, Kliniskt Forsknings Centrum	Umea
Sweden	Akademiska Sjukhuset, Kardiologen 50F/Forskningsenheten	Uppsala
Switzerland	Universitaetsspittal Zuerich, Medizinische Klinik A	Zuerich
United States	UT Southwestern Medical Center - Department of Internal Medicine Pulmonary	Dallas	Texas
United States	UT Southwestern St. Paul Hospital	Dallas	Texas
United States	Shands at University of Florida	Gainesville	Florida
United States	Creighton University Medical Center	Omaha	Nebraska
United States	John C. Lincoln Hospital, North Mountain	Phoenix	Arizona
United States	Pulmonary Associates, PA	Phoenix	Arizona
United States	Pulmonary Associates, PA	Phoenix	Arizona
United States	Allegheny General Hospital	Pittsburgh	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Pfizer

Countries where clinical trial is conducted

United States,  Canada,  Germany,  India,  Russian Federation,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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>	Baseline up-to follow up (Day 3 to 5)
Secondary	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)
Secondary	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
Secondary	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)

External Links

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