To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.

A MULTINATIONAL, MULTICENTRE, RANDOMIZED, PARALLEL GROUP, DOUBLE-BLIND STUDY TO ASSESS THE EFFICACY AND SAFETY OF 1MG, 5MG AND 20 MG TID OF ORAL SILDENAFIL IN THE TREATMENT OF SUBJECTS AGED 18 YEARS AND OVER WITH PULMONARY ARTERIAL HYPERTENSION (PAH)

To demonstrate a dose response for 1 mg, 5 mg and 20 mg TID oral sildenafil for the treatment of subjects with PAH.

Study Overview

• Status: Terminated
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Sildenafil citrate; Drug: Sildenafil citrate; Drug: Sildenafil citrate; Drug: Sildenafil citrate

• Study Type: Interventional
• Enrollment (Actual): 130
• Phase: Phase 4

Contacts and Locations

Study Locations

• Belgium
  • Leuven, Belgium, 3000
    • Universitaire Ziekenhuizen Leuven - Campus Gasthuisberg
• Brazil
  • RS
    • Porto Alegre, RS, Brazil, 90610-000
      • Hospital Sao Lucas da PUCRS
  • SP
    • Sao Paulo, SP, Brazil, 04012-909
      • Instituto Dante Pazzanese de Cardiologia
• Bulgaria
  • Sofia, Bulgaria, 1233
    • Peta mnogoprofilna bolnitsa za aktivno lechenie, Klinika po kardiologia
  • Sofia, Bulgaria, 1606
    • Mnogoprofilna bolnitsa za aktivno lechenie i speshna meditsina "N.I.Pirogov"
• China
  • Beijing, China, 100038
    • Beijing Shijitan Hospital
  • Shanghai, China, 200433
    • Shanghai Pulmonology Hospital
• Greece
  • Athens
    • Haidari, Athens, Greece, 12462
      • Attikon Hospital
• India
  • Andhra Pradesh
    • Hyderabad, Andhra Pradesh, India, 500 001
      • Care Hospital, The Institute of Medical Sciences
  • Gujarat
    • Ahmedabad, Gujarat, India, 380 054
      • Mehta Hospital & Cardiopulmonary Care Center
    • Vadodara, Gujarat, India, 390 015
      • Bankers Heart Institute
  • Karnataka
    • Bangalore, Karnataka, India, 560 034
      • St. John's Medical College Hospital
  • Uttar Pradesh
    • Noida, Uttar Pradesh, India, 201301
      • Metro Multispeciality Hospital
• Italy
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo
  • Roma, Italy, 00161
    • Unita' di Ipertensione Polmonare, Dipartimento di Scienze Respiratorie e Cardiovascolari
• Latvia
  • Riga, Latvia, LV - 1002
    • P. Stradins Clinical University Hospital / Latvian Centre of Cardilogy
• Malaysia
  • Kuala Lumpur, Malaysia, 50400
    • National Heart Institute
• Netherlands
  • Amsterdam, Netherlands, 1081 HV
    • VU Medisch Centrum / afdeling Longziekten
  • Rotterdam, Netherlands, 3015 GE
    • Erasmus MC
• Philippines
  • Manila City, Philippines, 1000
    • Philippine General Hospital
  • Quezon City, Philippines, 1100
    • Philippine Heart Center
• Poland
  • Krakow, Poland, 31-202
    • Krakowski Szpital Specjalistyczny im. Jana Pawla II w Krakowie
  • Zabrze, Poland, 41-800
    • Samodzielny Publiczny Zaklad Opieki Zdrowotnej, Slaskie Centrum Chorob Serca
• Romania
  • Iasi, Romania, 700115
    • Spitalul Clinic de Pneumoftiziologie
  • Timis
    • Timisoara, Timis, Romania
      • Spitalul Clinic de Boli Infectioase si Pneumoftiziologie Dr. Victor Babes
• Russian Federation
  • Moscow, Russian Federation, 117931
    • Scientific Center of Cardiovascular surgery n.a. A.N.Bakoulev RAMS
  • Moscow, Russian Federation, 121552
    • Scientific Center of Cardiovascular surgery n.a. A.N.Bakoulev RAMS
• Thailand
  • Bangkok, Thailand, 10330
    • Department of Medicine,
  • Khon Kaen
    • Amphoe Mueang, Khon Kaen, Thailand, 40002
      • Division of Rheumatology Allergy and Immunology, Department of Medicine, Faculty of Medicine
• United Kingdom
  • Norfolk
    • Norwich, Norfolk, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospital
  • Tyne and Wear
    • Newcastle Upon Tyne, Tyne and Wear, United Kingdom, NE7 7DN
      • Room 224A Sir William Leech Centre
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialists, Ltd
  • Georgia
    • Augusta, Georgia, United States, 30912
      • Medical College of Georgia
    • Decatur, Georgia, United States, 30030
      • Atlanta Institute for Medical Research, Inc.
  • Illinois
    • Elk Grove Village, Illinois, United States, 60007
      • Chicago Heart Institute
  • Indiana
    • Indianapolis, Indiana, United States, 46260
      • The Care Group, Llc
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • The University of North Carolina at Chapel Hill
    • Charlotte, North Carolina, United States, 28204
      • Presbyterian Hospital
    • Charlotte, North Carolina, United States, 28204
      • Mid Carolina Cardiology
  • Texas
    • Houston, Texas, United States, 77030
      • St. Luke's Episcopal Hospital
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine Pulmonary Section
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Sciences Center
  • Virginia
    • Richmond, Virginia, United States, 23225
      • Pulmonary Associates of Richmond, Inc.
    • Richmond, Virginia, United States, 23225
      • CJW Chippenham Medical Center
    • Richmond, Virginia, United States, 23225
      • Virginia Cardiovascular Specialists
    • Richmond, Virginia, United States, 23230
      • Cardiovascular Associates of Virginia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subjects with PAH (i.e. IPAH or secondary to connective tissue disease or with surgical repair of ASD, VSD, PDA, aorto-pulmonary window) whose baseline six minute walk test distance is >/= 100 m and </= 450 m.
• Subjects with a mean pulmonary artery pressure of >/= 25 mmHg and a pulmonary artery wedge pressure of </= 15 mmHg at rest via right heart catheterization performed within 12 weeks prior to randomization.

Exclusion Criteria:

• Subjects whose 6 Minute Walk Distance may be limited by conditions other than PAH related dyspnoea or fatigue, e.g. claudication from vascular insufficiency or significant arthritis.
• Subjects who are currently receiving any forms of chronic treatment for PAH such as prostacyclin, PDE-5 inhibitors, endothelin-receptor antagonists, nitrates or nitric oxide donors (e.g. arginine supplement, nicorandil) in any form, protease inhibitors such as ritonavir and saquinavir, ketoconazole, itraconazole, and alpha blockers. Subjects previously receiving any of these drugs must have stopped use for a period of at least 1 month prior to screening, except in the case of bosentan or prostacyclin (3 months).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sildenafil High dose	Drug: Sildenafil citrate; oral, 20 mg, tid; Drug: Sildenafil citrate; oral 1 mg, tid; Drug: Sildenafil citrate; oral 5 mg, tid; Drug: Sildenafil citrate; oral 20 mg, tid
Experimental: Sildenafil Low dose	Drug: Sildenafil citrate; oral, 20 mg, tid; Drug: Sildenafil citrate; oral 1 mg, tid; Drug: Sildenafil citrate; oral 5 mg, tid; Drug: Sildenafil citrate; oral 20 mg, tid
Experimental: Sildenafil medium dose	Drug: Sildenafil citrate; oral, 20 mg, tid; Drug: Sildenafil citrate; oral 1 mg, tid; Drug: Sildenafil citrate; oral 5 mg, tid; Drug: Sildenafil citrate; oral 20 mg, tid
Experimental: Sildenafil - Open label Phase; Open label extension from week 12 to week 24.	Drug: Sildenafil citrate; oral, 20 mg, tid; Drug: Sildenafil citrate; oral 1 mg, tid; Drug: Sildenafil citrate; oral 5 mg, tid; Drug: Sildenafil citrate; oral 20 mg, tid

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Total Distance Walked During 6-Minute Walk Test (6MWT) at Week 12	6 MWT was the distance that a participant could walk in 6 minutes. Participants were asked to perform the test at a pace that was comfortable to them, with as many breaks as they needed. Continuous pulse oximetry was conducted during the test for safety.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 12	mPAP was measured using a pressure transducer positioned at the mid-axillary line.	Baseline and Week 12
Number of Participants With Clinical Worsening	Clinical worsening was defined as death; or lung transplantation; or hospitalization due to pulmonary hypertension; or initiation of prostacyclin therapy; or initiation of endothelin receptor antagonist therapy. (PAH=pulmonary arterial hypertension) Due to very low number of events of clinical worsening reported, the median days to clinical worsening could not be estimated.	Baseline through Week 12
Number of Participants With Change From Baseline in PAH Criteria for Functional Capacity and Therapeutic Class at Week 12	Pulmonary arterial hypertension (PAH) Criteria for WHO Class: Class I (Participants without resulting limitation of physical activity);Class II (Participants with slight limitation of physical activity though comfortable at rest);Class III (Participants with marked limitation of physical activity,though comfortable at rest);Class IV(Participants with inability to carry out any physical activity without symptoms,manifest signs of right heart failure; dyspnoea and/or fatigue may even be present at rest; and discomfort is increased by any physical activity).	Baseline and Week 12
Change From Baseline in B-Type Natriuretic Peptide (BNP) at Week 12	BNP is a non-invasive biomarker and an indicator of progression of PAH/ right ventricular dysfunction in participants with PAH.	Baseline and Week 12
Change From Baseline in Pro-BNP at Week 12	Pro- BNP which is a precursor of BNP, is a non-invasive biomarker and an indicator of progression of PAH / RV dysfunction in participants with PAH.	Baseline and Week 12
Change From Baseline in TAPSE Measurement at Week 12	Tricuspid annular plane systolic excursion (TAPSE) was measured as the total displacement of the tricuspid annulus in cm from end diastole to end systole.TAPSE is an indicator of progression of PAH /right ventricular dysfunction. The baseline data for 33 participants were measured incorrectly and the results from the 33 participants (both baseline and post-baseline) were excluded from the analysis.	Baseline and Week 12
Change From Baseline in BORG Dyspnoea Score at Week 12	BORG dyspnoea scale is a 10-point scale where following scores stands for severity of dyspnoea: 0 (no breathlessness at all); 0.5 (very very slight [just noticeable]); 1 (very slight); 2 (slight breathlessness); 3 (moderate); 4 (some what severe); 5 (severe breathlessness); 7 (very severe breathlessness); 9 (very very severe [almost maximum] and 10 (maximum).	Baseline and Week 12

Collaborators and Investigators

• Sponsor: Pfizer's Upjohn has merged with Mylan to form Viatris Inc.

Publications and helpful links

General Publications

• Vizza CD, Sastry BK, Safdar Z, Harnisch L, Gao X, Zhang M, Lamba M, Jing ZC. Efficacy of 1, 5, and 20 mg oral sildenafil in the treatment of adults with pulmonary arterial hypertension: a randomized, double-blind study with open-label extension. BMC Pulm Med. 2017 Feb 23;17(1):44. doi: 10.1186/s12890-017-0374-x.

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2008
• Primary Completion (Actual): May 25, 2010
• Study Completion (Actual): May 25, 2010

Study Registration Dates

• First Submitted: January 31, 2007
• First Submitted That Met QC Criteria: January 31, 2007
• First Posted (Estimate): February 2, 2007

Study Record Updates

• Last Update Posted (Actual): December 22, 2020
• Last Update Submitted That Met QC Criteria: December 18, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Anticoagulants; Phosphodiesterase Inhibitors; Chelating Agents; Sequestering Agents; Phosphodiesterase 5 Inhibitors; Calcium Chelating Agents; Sildenafil Citrate; Citric Acid; Sodium Citrate
• Other Study ID Numbers: A1481244; 2006-006748-76 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.