Multinational Study of Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis (TETON-2)

A Randomized, Double-blind, Placebo-controlled, Multinational, Phase 3 Study of the Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis (TETON-2)

Study RIN-PF-303 is a multinational study designed to evaluate the superiority of inhaled treprostinil against placebo for the change in absolute forced vital capacity (FVC) from baseline to Week 52.

Study Overview

• Status: Completed
• Conditions: Idiopathic Pulmonary Fibrosis; Interstitial Lung Disease
• Intervention / Treatment: Drug: Placebo; Device: Treprostinil Ultrasonic Nebulizer; Drug: Inhaled Treprostinil

Detailed Description

Study RIN-PF-303 is a multinational, randomized, double-blind, placebo-controlled study to evaluate the superiority of inhaled treprostinil against placebo for the change in absolute FVC in subjects with IPF over a 52-week period. Subjects will be randomly allocated 1:1 to receive inhaled treprostinil or placebo. All subjects will initiate inhaled treprostinil or placebo at a dose of 3 breaths administered 4 times daily (QID) and will titrate to a target dosing regimen of 12 breaths QID. Study drug doses may be titrated up as tolerated, until the target dose or maximum clinically tolerated dose is achieved. Once eligible, 6 Treatment Period visits to the clinic will be required at Weeks 4, 8, 16, 28, 40, and 52.

Efficacy assessments include spirometry (FVC), time to clinical worsening, time to first acute exacerbation of IPF, overall survival, King's Brief Interstitial Lung Disease (K-BILD) questionnaire, plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, supplemental oxygen use, and lung diffusion capacity (DLCO). Safety assessments include the development of adverse events (AEs)/serious adverse events (SAEs), vital signs, clinical laboratory parameters, and electrocardiogram (ECG) parameters.

Subjects who complete the Week 52 Visit may be offered the opportunity to enter an open-label extension (OLE) study after completing the final study visit.

• Study Type: Interventional
• Enrollment (Actual): 597
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Cordoba, Argentina, 5021
    • Sanatorio Allende S.A.
  • Mendoza, Argentina, 5500
    • Centro Médico INSARES
  • Buenos Aires
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1027AAP
      • CINME S.A. - Centro de Investigaciones Metabólicas
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1426ABP
      • Centro Médico Dra. De Salvo
    • Mar del Plata, Buenos Aires, Argentina, 7600
      • Instituto Ave Pulmo - Fundación enfisema
  • Cordoba
    • Río Cuarto, Cordoba, Argentina, 5800
      • Instituto Medico Río Cuarto
  • Santa Fe
    • Rosario, Santa Fe, Argentina, 2000
      • Sanatorio Parque - Consultorios Externos
  • Tucuman
    • San Miguel de Tucuman, Tucuman, Argentina, 4000
      • Centro Integral de Medicina Respiratoria
    • San Miguel de Tucuman, Tucuman, Argentina, 4000
      • Investigaciones en Patologías Respiratorias
• Australia
  • New South Wales
    • Camperdown, New South Wales, Australia, 2050
      • Royal Prince Alfred Hospital, Missenden Road
    • Macquarie Park, New South Wales, Australia, 2109
      • Macquarie University
    • Westmead, New South Wales, Australia, 2145
      • Westmead Hospital, Corner of Hawkesbury and Darcy Road
  • Queensland
    • Cairns, Queensland, Australia, 5870
      • Cairns Hospital
    • Chermside, Queensland, Australia, 4032
      • Prince Charles Hospital
    • Chermside, Queensland, Australia, 4032
      • Lung Research Qld
    • South Brisbane, Queensland, Australia, 4101
      • Mater Misericordiae Ltd
  • South Australia
    • Kent Town, South Australia, Australia, 5067
      • Respiratory Clinical Trials PTY Ltd
  • Victoria
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
    • Melbourne, Victoria, Australia, 3004
      • Austin Health
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Institute for Respiratory Health - Midland
    • Nedlands, Western Australia, Australia, 6009
      • Institute for Respiratory Health - Nedlands
• Belgium
  • Aalst, Belgium, 9300
    • AZORG vzw
  • Antwerpen, Belgium, 2020
    • Ziekenhuis Aan de Stroom
  • Brussels, Belgium, 1200
    • Cliniques Universitaires Saint-Luc
  • Leuven, Belgium, 3000
    • UZ Leuven
  • Liège, Belgium, 4000
    • CHU de Liège
  • Liège, Belgium, 4000
    • CHR de la Citadelle
  • Brussels
    • Anderlecht, Brussels, Belgium, 1070
      • Hôpital Erasme
  • Namur
    • Yvoir, Namur, Belgium, 5530
      • CHU UCl Namur asbl - Site Godinne
• Chile
  • Maule
    • Talca, Maule, Chile, 3465586
      • Centro de Investigación del Maule SpA
  • Region Metropolitana
    • Santiago, Region Metropolitana, Chile, 7630000
      • Fundación Médica San Cristobal
  • Región Metropolitana
    • Santiago, Región Metropolitana, Chile, 7500691
      • Instituto Nacional Torax
  • Valparaiso
    • Viña del Mar, Valparaiso, Chile, 2520598
      • Oncocentro Apys
• Denmark
  • Aarhus N, Denmark, 8200
    • Aarhus University Hospital - Department of Respiratory Diseases and Allergy, Research Unit
  • Hellerup, Denmark, 2900
    • Gentofte Hospital - Lungemedicinsk forskning
  • Odense C, Denmark, 5000
    • Odense University Hospital - Department of Respiratory Medicine J.
• France
  • Amiens Cedex 1, France, 80054
    • CHU Amiens Picardie Site Sud - Service de Pneumologie
  • Caen, France, 14033
    • Hôpital Côte de Nacre
  • Lyon, France, 69677 Cedex
    • Groupement Hospitalier EST, Service de Pneumologie
  • Marseille, France, 13015
    • APHM-Hôpital Nord
  • Paris, France, 75018
    • Hôpital Bichat
  • Paris, France, 75015
    • Service de Pneumologie, Hôpital Européen Georges Pompídou (HEGP)
  • Reims Cedex, France, 51092
    • CHU Reims - Hôpital Maison Blanche
  • Rouen, France, 76000
    • Hopital Charles Nicolle-1 Rue de Germont
  • Rouen cedex, France, 76031
    • CHU de Rouen - Hôpital Charles Nicolle
  • TOURS Cedex 9, France, 37044
    • CHRU Tours - Hôpital Bretonneau
  • Toulouse Cedex 9, France, 31059
    • Hopital Larrey
  • Ille-et-Vilaine
    • Rennes, Ille-et-Vilaine, France, 35033
      • Hôpital Pontchaillou
  • Seine-Saint Denis
    • Bobigny, Seine-Saint Denis, France, 93000
      • Hôpital Avicenne
• Germany
  • Bad Berka, Germany, 99437
    • Zentralklinik Bad Berka GmbH
  • Coswig, Germany, 01640
    • Fachkrankenhaus Coswig
  • München, Germany, 81377
    • LMU Klinikum der Universität
  • Baden-Württemberg
    • Löwenstein, Baden-Württemberg, Germany, 74245
      • Klinik Löwenstein GmbH
  • Bayern
    • Rosenheim, Bayern, Germany, 83022
      • RoMed Klinikum Rosenheim
  • Nordrhein-Westfalen
    • Essen, Nordrhein-Westfalen, Germany, 45239
      • Universitätsmedezin Essen Ruhrlandklinik Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH
• Israel
  • Hadera, Israel, 38100
    • Hillel Yaffe Medical Center
  • Haifa, Israel, 34362
    • Lady Davis Carmel Medical Center
  • Haifa, Israel, 3109601
    • Rambam Medical Center - PPDS
  • Petah Tiqva, Israel, 4910000
    • Rabin Medical Center - PPDS
  • HaDarom
    • Tel Aviv, HaDarom, Israel, 64239
      • Tel Aviv Sourasky Medical Center - PPDS
  • HaMerkaz
    • Kfar Sava, HaMerkaz, Israel, 44281
      • Meir Medical Center
    • Rehovot, HaMerkaz, Israel, 76100
      • Kaplan Medical Center
  • Tel-Aviv
    • Ramat Gan, Tel-Aviv, Israel, 52621
      • Sheba Medical Center - PPDS
    • Ramat-Gan, Tel-Aviv, Israel, 52621
      • Sheba Medical Center - PPDS
  • Yerushalayim
    • Jerusalem, Yerushalayim, Israel, 91120
      • Hadassah Medical Center - PPDS
    • Jerusalem, Yerushalayim, Israel, 9103102
      • Shaare Zedek Medical Center
• Italy
  • Ancona, Italy, 60126
    • Azienda Ospedaliero-Universitaria delle Marche
  • Modena, Italy, 41124
    • Azienda Ospedaliero Universitaria Di Modena Policlinico
  • Roma, Italy, 00168
    • Fondazione Policlinico Universitario A Gemelli-Rome
  • Rome, Italy, 00133
    • Fondazione PTV Policlinico Tor Vergata
  • Emilia-Romagna
    • Forli, Emilia-Romagna, Italy, 47121
      • Presidio Ospedaliero GB Morgagni L Pierantoni
  • Lombardia
    • Milano, Lombardia, Italy, 20123
      • Ospedale S. Giuseppe Multimedica
  • Sicilia
    • Catania, Sicilia, Italy, 95123
      • Azienda Ospedaliero Universitaria Policlinico "G.Rodolico-San Marco"
  • Toscana
    • Siena, Toscana, Italy, 53100
      • Azienda Ospedaliera Universitaria Senese
• Korea, Republic of
  • Incheon, Korea, Republic of, 21565
    • Gachon University Gil Medical Center
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital
  • Seoul, Korea, Republic of, 06351
    • Samsung Medical Center - PPDS
  • Seoul, Korea, Republic of, 03312
    • The Catholic University of Korea - Eunpyeong St. Mary's Hospital
  • Gyeonggido
    • Seongnam-si, Gyeonggido, Korea, Republic of, 13620
      • Seoul National University Bundang Hospital
    • Seongnam-si, Gyeonggido, Korea, Republic of, 13496
      • CHA Bundang Medical Center, CHA University
  • Seoul Teugbyeolsi
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 05505
      • Asan Medical Center
    • Seoul, Seoul Teugbyeolsi, Korea, Republic of, 7061
      • SMG - SNU Boramae Medical Center
• Mexico
  • Ciudad de México, Mexico, 14080
    • Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
    • Monterrey, Nuevo León, Mexico, 64060
      • Unidad de Investigación Clínica en Medicina, S.C.
• Netherlands
  • Limburg
    • Heerlen, Limburg, Netherlands, 6419 PC
      • Zuyderland Medisch Centrum
  • Utrecht
    • Nieuwegein, Utrecht, Netherlands, 3435 CM
      • St. Antonius Ziekenhuis
  • Zuid-Holland
    • Rotterdam, Zuid-Holland, Netherlands, 3015 GD
      • Erasmus MC
• New Zealand
  • Canterbury
    • Christchurch, Canterbury, New Zealand, 8013
      • Canterbury Respiratory Research Group
  • Waikato
    • Hamilton, Waikato, New Zealand, 3204
      • Respiratory Medicine
• Peru
  • Lima, Peru, 15036
    • Clinica Ricardo Palma
  • Lima, Peru, 15046
    • Hospital Central de la Fuerza Aérea del Perú
  • Cusco
    • Wanchaq, Cusco, Peru, 8003
      • Hospital Nacional Adolfo Guevara Velasco
  • Lima
    • Huaral, Lima, Peru, 15131
      • Hospital de Chancay y Servicios Basicos deSalud
• Spain
  • Barcelona, Spain, 08036
    • Hospital Clínic de Barcelona
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Granada, Spain, 18014
    • Hospital Universitario Virgen de Las Nieves
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Maranon
  • Murcia, Spain, 30120
    • Hospital Clinico Universitario Virgen de La Arrixaca
  • Santander, Spain, 39008
    • Hospital Universitario Marques de Valdecilla
  • Santiago de Compostela, Spain, 15706
    • Hospital Clinico Universitario de Santiago
  • Asturias
    • Oviedo, Asturias, Spain, 33011
      • Hospital Universitario Central de Asturias
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08907
      • Hospital Universitario de Bellvitge
  • Islas Baleares
    • Palma De Mallorca, Islas Baleares, Spain, 07120
      • Hospital Universitario Son Espases
• Taiwan
  • Kaohsiung, Taiwan, 82445
    • E-DA hospital
  • New Taipei City, Taiwan, 220
    • Far Eastern Memorial Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • Samin District
    • Kaohsiung, Samin District, Taiwan, 80756
      • Kaohsiung Medical University - Chung-Ho Memorial Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Subject gives voluntary informed consent to participate in the study.
2. Subject is ≥40 years of age, inclusive, at the time of signing informed consent.
3. The subject has a diagnosis of IPF based on the 2018 ATS/ERS/JRS/ALAT Clinical Practice Guideline (Raghu 2018) and confirmed by central review of high-resolution computed tomography (HRCT) (performed within the previous 12 months), and if available, surgical lung biopsy.
4. FVC ≥45% predicted at Screening.
5. Subjects on pirfenidone or nintedanib must be on a stable and optimized dose for ≥30 days prior to Baseline. Concomitant use of both pirfenidone and nintedanib is not permitted.
6. Women of childbearing potential must be non-pregnant (as confirmed by a urine pregnancy test at Screening and Baseline) and non-lactating, and will abstain from intercourse (when it is in line with their preferred and usual lifestyle) or use 2 medically acceptable, highly effective forms of contraception for the duration of the study, and at least 30 days after discontinuing study drug.
7. Males with a partner of childbearing potential must use a condom for the duration of treatment and for at least 48 hours after discontinuing study drug.
8. In the opinion of the Investigator, the subject is able to communicate effectively with study personnel, and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.

Exclusion Criteria:

1. Subject is pregnant or lactating.
2. Subject has primary obstructive airway physiology: FEV1/FVC <0.70 at Screening.
3. The subject has shown intolerance or significant lack of efficacy to a prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to effectively titrate that therapy.
4. The subject has received any PAH-approved therapy, including prostacyclin therapy (epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), IP receptor agonists (selexipag), endothelin receptor antagonists, phosphodiesterase type 5 inhibitors (PDE5-Is), or soluble guanylate cyclase stimulators within 60 days prior to Baseline. As needed use of a PDE5-I for erectile dysfunction is permitted, provided no doses are taken within 48 hours of any study-related efficacy assessments.
5. Use of any of the following medications: azathioprine (AZA), cyclosporine, mycophenolate mofetil, tacrolimus, oral corticosteroids (OCS) >20 mg/day or the combination of OCS+AZA+N-acetylcysteine within 30 days prior to Baseline; cyclophosphamide within 60 days prior to Baseline; or rituximab within 6 months prior to Baseline.
6. The subject is receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline.
7. Exacerbation of IPF or active pulmonary or upper respiratory infection within 30 days prior to Baseline. Subjects must have completed any antibiotic or steroid regimens for treatment of the infection or acute exacerbation more than 30 days prior to Baseline to be eligible. If hospitalized for an acute exacerbation of IPF or a pulmonary or upper respiratory infection, subjects must have been discharged more than 90 days prior to Baseline to be eligible.
8. Uncontrolled cardiac disease, defined as myocardial infarction within 6 months prior to Baseline or unstable angina within 30 days prior to Baseline.
9. In the opinion of the Investigator, the subject has any condition that would interfere with the interpretation of study assessments or would impair study participation or cooperation.
10. Use of any other investigational drug/device or participation in any investigational study in which the subject received a medical intervention (ie, procedure, device, medication/supplement) within 30 days prior to Screening. Subjects participating in non-interventional, observational, or registry studies are eligible.
11. Life expectancy <6 months due to IPF or a concomitant illness.
12. Acute pulmonary embolism within 90 days prior to Baseline.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Matching placebo inhaled using an ultrasonic nebulizer QID	Drug: Placebo; Placebo administered QID; Device: Treprostinil Ultrasonic Nebulizer; Treprostinil ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath.
Experimental: Inhaled Treprostinil; Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled QID and titrated up to a target of 12 breaths QID or until the subject reaches their maximum clinically tolerated dose.	Device: Treprostinil Ultrasonic Nebulizer; Treprostinil ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath.; Drug: Inhaled Treprostinil; Inhaled treprostinil (6 mcg/breath) administered QID; Other Names: Tyvaso

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Absolute FVC from Baseline to Week 52	The FVC measurement indicates the amount of air a person can forcefully and quickly exhale after taking a deep breath.	Baseline to Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Clinical Worsening	Clinical worsening was monitored from randomization until 1 of the following criteria were met: death (all causes), hospitalization due to a respiratory indication, or 10% relative decline in % predicted FVC.	Baseline to Week 52
Time to First Acute Exacerbation of IPF	An exacerbation of IPF is defined as an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality.	Baseline to Week 52
Overall Survival at Week 52	Vital status will be assessed for all subjects at Week 52, including those who discontinue the study prematurely or who withdraw consent.	Baseline to Week 52
Change in % Predicted FVC from Baseline to Week 52	The FVC measurement indicates the amount of air a person can forcefully and quickly exhale after taking a deep breath. Percent predicted FVC is calculated based on factors such as ethnicity, sex, age, height, and weight.	Baseline to Week 52
Change in K-BILD Questionnaire Score from Baseline to Week 52	The K-BILD is a self-administered, 15-item questionnaire validated for patients with interstitial lung disease (ILD) consisting of 3 domains (breathlessness and activities, psychological, and chest symptoms).	Baseline to Week 52
Change in DLCO from Baseline to Week 52	The DLCO measurement measures how well oxygen moves from the lungs to the blood.	Baseline to Week 52

Collaborators and Investigators

• Sponsor: United Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): October 4, 2022
• Primary Completion (Actual): June 30, 2025
• Study Completion (Actual): June 30, 2025

Study Registration Dates

• First Submitted: February 15, 2022
• First Submitted That Met QC Criteria: February 15, 2022
• First Posted (Actual): February 25, 2022

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 11, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: ILD; Treprostinil; IPF
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Pulmonary Fibrosis; Idiopathic Pulmonary Fibrosis; Fibrosis; Lung Diseases, Interstitial; Antihypertensive Agents; Treprostinil
• Other Study ID Numbers: RIN-PF-303; 2021-005881-17 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No