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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

Primary Purpose

Hypertension, Pulmonary

Status

Terminated

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

PF-00489791

placebo

sildenafil

About this trial

This is an interventional treatment trial for Hypertension, Pulmonary focused on measuring PAH pulmonary hypertension pulmonary arterial hypertension

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

Pulmonary Associates, PA
John C. Lincoln Hospital, North Mountain
Pulmonary Associates, PA
Shands at University of Florida
Creighton University Medical Center
Allegheny General Hospital
UT Southwestern Medical Center - Department of Internal Medicine Pulmonary
UT Southwestern St. Paul Hospital
Lawson Health Research Institute
London Health Sciences Centre
Sir Mortimer B. Davis, Jewish General Hospital
Thoraxklinik am Universitaetsklinikum
Department Of Cardiology, MediCiti Hospital,
Department Of Cardiology, Sri Venkateswara Institute Of Medical Sciences
Bankers Heart Institute
Omega Hospital
Moscow Healthcare Institution "City Clinical Hospital No. 57"
Institute of Cardiosurgery n.a. V.I.Burakovsky
Hospital General Universitari Vall D´Hebron
Hospital Clinic I Provincial
Hospital Universitario 12 de Octubre
Universitetssjukhuset i Lund, Hjart- och Lungdivisionen
Norrlands Universitetssjukhus, Kliniskt Forsknings Centrum
Akademiska Sjukhuset, Kardiologen 50F/Forskningsenheten
Universitaetsspittal Zuerich, Medizinische Klinik A

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Placebo Comparator

Active Comparator

Arm Label

PF-00489791 1 mg

PF-00489791 2 mg

PF-00489791 4 mg

PF-00489791 10 mg

PF-00489791 20 mg

Placebo

Sildenafil

Arm Description

Observational comparator arm

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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.

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.

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.

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.

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.

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.

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).

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.

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).

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.

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.

Plasma Concentration of PF-00489791 and Sildenafil

Full Information

NCT ID

NCT00853112

First Posted

February 27, 2009

Last Updated

September 20, 2017

Sponsor

Pfizer

1. Study Identification

Unique Protocol Identification Number

NCT00853112

Brief Title

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

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2017

Overall Recruitment Status

Terminated

Why Stopped

See termination reason in detailed description.

Study Start Date

April 2009 (Actual)

Primary Completion Date

July 2010 (Actual)

Study Completion Date

July 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Pfizer

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

Detailed 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hypertension, Pulmonary

Keywords

PAH pulmonary hypertension pulmonary arterial hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

48 (Actual)

8. Arms, Groups, and Interventions

Arm Title

PF-00489791 1 mg

Arm Type

Experimental

Arm Title

PF-00489791 2 mg

Arm Type

Experimental

Arm Title

PF-00489791 4 mg

Arm Type

Experimental

Arm Title

PF-00489791 10 mg

Arm Type

Experimental

Arm Title

PF-00489791 20 mg

Arm Type

Experimental

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Title

Sildenafil

Arm Type

Active Comparator

Arm Description

Observational comparator arm

Intervention Type

Drug

Intervention Name(s)

PF-00489791

Intervention Description

tablet form, 1 mg, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

PF-00489791

Intervention Description

tablet form, 2 mg, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

PF-00489791

Intervention Description

tablet form, 4 mg, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

PF-00489791

Intervention Description

tablet form, 10 mg, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

PF-00489791

Intervention Description

tablet form, 20 mg, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

placebo

Intervention Description

tablet form, single dose (Day 1)

Intervention Type

Drug

Intervention Name(s)

sildenafil

Other Intervention Name(s)

Revatio

Intervention Description

tablet form, 20 mg, single dose (Day 1)

Primary Outcome Measure Information:

Title

Mean Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) Over 4 Hours Post Dose

Description

Time Frame

Baseline, up to 4 hours post-dose on Day 1

Secondary Outcome Measure Information:

Title

Greatest Reduction From Baseline in Pulmonary Vascular Resistance Index (PVRI) and Systemic Vascular Resistance Index (SVRI) Over 4 Hours Post Dose

Description

Time Frame

Baseline, up to 4 hours post-dose on Day 1

Title

Mean Change From Baseline in Systemic Vascular Resistance Index (SVRI) Over 4 Hours Post Dose

Description

Time Frame

Baseline, up to 4 hours post-dose on Day 1

Title

Change From Baseline in Pulmonary Vascular Resistance Index (PVRI) at Hour 1, 2, 3 and 4 Post Dose

Description

Time Frame