Effects of Oral Sildenafil on Mortality in Adults With PAH (AFFILIATE)

A MULTINATIONAL, MULTICENTER STUDY TO ASSESS THE EFFECTS OF ORAL SILDENAFIL ON MORTALITY IN ADULTS WITH PULMONARY ARTERIAL HYPERTENSION (PAH)

This is a blinded study in adult patients with PAH evaluating the relative effects of sildenafil on mortality when administered at the three doses (80 mg, 20 mg or 5 mg, all three times per day [TID]). In addition, the relative effects on clinical worsening and 6-minute walking distance (6MWD) will be assessed.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 385
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital
  • Queensland
    • Herston, Queensland, Australia, 4029
      • Royal Brisbane & Women's Hospital
  • South Australia
    • Bedford Park, South Australia, Australia, 5042
      • Australian Respiratory and Sleep Medicine Institute
• Belgium
  • Yvoir, Belgium, 5530
    • University Hospital of Mont-Godinne
• Bosnia and Herzegovina
  • B&h/republic OF Srpska
    • Banja Luka, B&h/republic OF Srpska, Bosnia and Herzegovina, 78000
      • University Clinical Center of the Republic of Srpska
  • Bosnia AND Herzegovina/canton Sarajevo
    • Sarajevo, Bosnia AND Herzegovina/canton Sarajevo, Bosnia and Herzegovina, 71000
      • Clinical Center University Sarajevo
  • Canton Tuzla
    • Tuzla, Canton Tuzla, Bosnia and Herzegovina, 75000
      • Health Institution Special Hospital "Medical Institute Bayer"
  • Herzegovina-neretva Canton
    • Mostar, Herzegovina-neretva Canton, Bosnia and Herzegovina, 88000
      • University Clinical Hospital Mostar
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Dubrava
  • Zagreb, Croatia, 10 000
    • University Hospital Center Zagreb
• Czechia
  • Olomouc, Czechia, 779 00
    • Fakultni Nemocnice Olomouc
  • Praha 4, Czechia, 140 21
    • Institut Klinicke a Experimentalni Mediciny
  • Czech Republic
    • Praha 2, Czech Republic, Czechia, 128 08
      • Vseobecna Fakultni Nemocnice V Praze
• Germany
  • Berlin, Germany, 14050
    • DRK Kliniken Berlin, Westend
  • Dresden, Germany, 01307
    • Universitaetsklinikum der TU Dresden
  • Dresden, Germany, 01307
    • Universitätsklinikum TU Dresden
  • Greifswald, Germany, 17475
    • Universitaetsmedizin Greifswald
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
  • Heidelberg, Germany, 69126
    • Thoraxklinik am Universitaetsklinikum Heidelberg
  • Luebeck, Germany, 23538
    • Universitaetsklinikum Schleswig-Holstein
• Greece
  • Patras, Greece, 26504
    • University General Hospital of Patras
  • Thessaloniki, Greece, 54636
    • University General Hospital of Thessaloniki AHEPA
  • Attiki
    • Athens, Attiki, Greece, 12462
      • University General Hospital of Athens "Attikon"
  • Evros
    • Alexandroupolis, Evros, Greece, 68100
      • University General Hospital of Alexandroupolis
• Hong Kong
  • Hong Kong, Hong Kong
    • Queen Mary Hospital
  • Shatin, New Territories, Hong Kong
    • Prince of Wales Hospital
• Israel
  • Tel-Hashomer, Israel, 5262000
    • The Chaim Sheba Medical Center
• Latvia
  • Riga, Latvia, LV-1002
    • Pauls Stradins Clinical University Hospital
• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • University Malaya Medical Centre
  • Johor
    • Johor Bahru, Johor, Malaysia, 80100
      • Hospital Sultanah Aminah
  • Kedah
    • Alor Setar, Kedah, Malaysia, 05460
      • Hospital Sultanah Bahiyah
  • Selangor
    • Kajang, Selangor, Malaysia, 43000
      • Hospital Serdang
• Mexico
  • Queretaro, Mexico, 76000
    • Centro de Estudios Clínicos de Querétaro S.C.
  • Nuevo LEÓN
    • Monterrey, Nuevo LEÓN, Mexico, 64460
      • Centro De Prevencion Y Rehabilitacion De Enfermedades Pulmonares Crónicas
  • Yucatan
    • Merida, Yucatan, Mexico, 97070
      • Centro de Desarrollo Biomedico
• Poland
  • Lublin, Poland, 20-954
    • Samodzielny Publiczny Szpital Kliniczny nr 4
• Romania
  • Cluj-Napoca, Romania, 400001
    • Institutul Inimii ,,Niculae Stancioiu" Cluj Napoca
  • Targu-Mures, Romania, 540136
    • Institutul de Urgenta pentru Boli Cardiovasculare si Transplant Targu-Mures
• Russian Federation
  • Kemerovo, Russian Federation, 650002
    • FSBI "Research Institute of complex problems of cardiovascular diseases"
  • Moscow, Russian Federation, 105077
    • FSBI Scientific Research Institute of Pulmonology of FMBA
  • Novosibirsk, Russian Federation, 630055
    • FSBI "E.Meshalkin National medical research center"
  • St. Petersburg, Russian Federation, 197341
    • FSBI "V.A. Almazov National Medical Research Center"
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Center of Serbia
  • Belgrade, Serbia, 11000
    • University Medical Center Zvezdara
  • Kragujevac, Serbia, 34 000
    • Clinical Center Kragujevac
  • Vojvodina
    • Sremska Kamenica, Vojvodina, Serbia, 21204
      • Institute for Cardiovascular Disease of Vojvodina
    • Sremska Kamenica, Vojvodina, Serbia, 21204
      • Institute for pulmonary diseases of Vojvodina
• Singapore
  • Singapore, Singapore, 768828
    • Khoo Teck Puat Hospital
  • Singapore, Singapore, 119228
    • National University Heart Centre, National University Hospital Singapore (NUHS)
• South Africa
  • Gauteng
    • Johannesburg, Gauteng, South Africa, 2193
      • Center of Chest Diseases
    • Johannesburg, Gauteng, South Africa, 2193
      • Dr PG Williams Practice
• Spain
  • Cataluña
    • Barcelona, Cataluña, Spain, 08035
      • Hospital Universitario Vall d´Hebron
• Thailand
  • Bangkok
    • Pathumwan, Bangkok, Thailand, 10330
      • Faculty of Medicine, Chulalongkorn University
    • Pathumwan, Bangkok, Thailand, 10330
      • King Chulalongkorn Memorial Hospital, Faculty of Medicine, Chulalongkorn University
  • Chiang MAI
    • Muang, Chiang MAI, Thailand, 50200
      • Maharaj Nakorn Chiang Mai Hospital
    • Sripoom Sub-district, Muang, Chiang MAI, Thailand, 50200
      • Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University
  • Khon Kaen
    • Muang District, Khon Kaen, Thailand, 40002
      • Division of Cardiology, Department of Medicine, Faculty of Medicine, Khon Kaen University
    • Muang District, Khon Kaen, Thailand, 40002
      • Queen Sirikit Heart Center of the Northeast, Khon Kaen University
    • Muang District, Khon Kaen, Thailand, 40002
      • Srinagarind Hospital, Faculty of Medicine, Khon Kaen University
• Turkey
  • Bakirkoy
    • Istanbul, Bakirkoy, Turkey, 34147
      • Bakirkoy Dr. Sadi Konuk Training and Research Hospital
  • Fatih
    • Istanbul, Fatih, Turkey, 34096
      • Istanbul University Cerrahpasa Medical Faculty
    • Istanbul, Fatih, Turkey, 34096
      • Istanbul University Haseki Cardiology Institute
  • Inciralti
    • Izmir, Inciralti, Turkey, 35340
      • Dokuz Eylul Üniversitesi Tıp Fakültesi Kardiyoloji Bilim Dalı
  • Pendik
    • Istanbul, Pendik, Turkey, 34899
      • Marmara University Pendik Training and Research Hospital
• Ukraine
  • Kharkiv,, Ukraine, 61176
    • Komunalne nekomertsiine pidpryiemstvo
  • Kyiv, Ukraine, 01601
    • Komunalne nekomertsiine pidpryiemstvo Oleksandrivska klinichna likarnia m. Kyieva
  • Kyiv, Ukraine, 03115
    • Komunalne nekomertsiine pidpryiemstvo
  • Kyiv, Ukraine, 03680
    • Derzhavna ustanova Natsionalnyi naukovyi tsentr
  • M. Dnipro, Ukraine, 49044
    • Komunalne pidpryiemstvo "Dnipropetrovskyi oblasnyi klinichnyi tsentr kardiolohii ta kardiokhirurhii"
  • Uzhhorod,, Ukraine, 88000
    • Komunalne nekomertsiine pidpryiemstvo
• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
    • Atlanta, Georgia, United States, 30322
      • Emory University Investigational Drug Services
  • Michigan
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Hospitals
    • Grand Rapids, Michigan, United States, 49546
      • Spectrum Health
    • Grand Rapids, Michigan, United States, 49503
      • Frederik Meijer Heart & Vascular Institute Cardiovascular Research
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Butterworth Hospital IDS Pharmacy
    • Grand Rapids, Michigan, United States, 49503
      • Spectrum Health Heart & Lung Specialized Care Clinic
    • Grand Rapids, Michigan, United States, 49546
      • Spectrum Health Medical Group - Pulmonary Division
  • Ohio
    • Wooster, Ohio, United States, 44691
      • Robert V. Sibilia MD, Inc.
  • Texas
    • Dallas, Texas, United States, 75390-8550
      • UT Southwestern Medical School
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • Aurora St. Luke's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Subjects ≥ 18 <75 years of age with any of the following conditions:

• Idiopathic Primary Pulmonary Arterial Hypertension (IPAH)
• PAH secondary to connective tissue disease
• PAH with surgical repair (at least 5 years previously) of atrial septal defect (ASD),ventricular septal defect (VSD), patent ductus arteriosus (PDA) and aorto-pulmonary window
• PAH diagnosis confirmed by right heart catheterization performed within 12 months prior to randomization
• Functional Class II-IV; Baseline 6MWD ≥ 50 m.

Exclusion Criteria:

• Significant (ie, >2+) valvular disease other than tricuspid regurgitation or pulmonary regurgitation
• History of cardiac arrest, respiratory arrest, hemodynamic collapse, CPR, ventricular tachycardia, ventricular fibrillation, or uncontrolled atrial fibrillation
• History of pulmonary embolism; History of chronic lung disease / restrictive lung disease (eg, chronic obstructive pulmonary disease (COPD) or scleroderma) with impairment of lung function
• No prior long term treatment with PDE-5 inhibitors
• Treatment with bosentan OR riociguat within 3 months of randomization
• Current treatment with nitrates or nitric oxide

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low dose	Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 20 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 80 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio
Experimental: High dose	Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 20 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 80 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio
Experimental: Medium dose	Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 5 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 20 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio; Drug: sildenafil citrate; sildenafil citrate (PDE-5 inhibitor) 80 mg tablet TID until study treatment discontinued or end of study; Other Names: Revatio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	In this outcome measure number of deaths during the study were reported.	Day 1 of study treatment up to date of death (within a maximum duration of 2102 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Clinical Worsening Events	Clinical worsening was defined as all-cause mortality, non-elective hospital stay for worsening pulmonary arterial hypertension (PAH) (including but not limited to right heart failure [RHF], initiation of intravenous (IV) prostanoids, lung transplantation, or septostomy) or disease progression. Disease progression was defined as a reduction from baseline in the 6-Minute Walk Distance (6MWD) test by 15% and worsening functional class from baseline, both confirmed by second test within 2 weeks of study treatment.	Day 1 of study treatment up to date of clinical worsening event (within a maximum duration of 2080 days)
Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 6	6MWD 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. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH.	Baseline, Month 6
Change From Baseline in 6-Minute Walk Distance (6MWD) at Month 12	6MWD 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. Analysis was performed using mixed model for repeated measures (MMRM), adjusted for baseline 6MWD and for randomization stratification factors: PAH treatment at study entry and etiology of PAH.	Baseline, Month 12

Collaborators and Investigators

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

Publications and helpful links

Helpful Links

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

Study record dates

Study Major Dates

• Study Start (Actual): September 22, 2014
• Primary Completion (Actual): February 26, 2021
• Study Completion (Actual): February 26, 2021

Study Registration Dates

• First Submitted: January 29, 2014
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimate): February 12, 2014

Study Record Updates

• Last Update Posted (Actual): May 13, 2022
• Last Update Submitted That Met QC Criteria: May 11, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Keywords: sildenafil; pulmonary hypertension; PAH; pulmonary arterial hypertension; revatio
• 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: A1481324; 2013-004362-34 (EudraCT Number); AFFILIATE (Other Identifier: Alias Study 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.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No