Idiopathic Pulmonary FibrosisPhase 3TETON-2NCT05255991
Multinational Study of Efficacy and Safety of Inhaled Treprostinil in Subjects With Idiopathic Pulmonary Fibrosis
A Phase 3 study testing Inhaled Treprostinil and Treprostinil Ultrasonic Nebulizer in people with Idiopathic Pulmonary Fibrosis and Interstitial Lung Disease, run by United Therapeutics at 108 sites in 16 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Idiopathic Pulmonary Fibrosis, Interstitial Lung Disease
- What is being tested?
- Inhaled Treprostinil and Treprostinil Ultrasonic Nebulizer
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 597 participants
- Where
- 108 sitesin 16 countries
- Study dates
- 12 Sep 2022to 30 Jun 2025
- Phase
- Phase 3
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Subject gives voluntary informed consent to participate in the study.
- Subject is ≥40 years of age, inclusive, at the time of signing informed consent.
- 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.
- FVC ≥45% predicted at Screening.
- 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.
- 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.
- 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.
- 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.
Who cannot join
- Subject is pregnant or lactating.
- Subject has primary obstructive airway physiology: FEV1/FVC <0.70 at Screening.
- 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.
- 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.
- 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.
- The subject is receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline.
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- 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.
- Uncontrolled cardiac disease, defined as myocardial infarction within 6 months prior to Baseline or unstable angina within 30 days prior to Baseline.
- 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.
- 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.
- Life expectancy <6 months due to IPF or a concomitant illness.
- Acute pulmonary embolism within 90 days prior to Baseline.
Trial locations and contacts
108 sites in 16 countries.
108 sites in 16 countries
France13 sites
CHU Amiens Picardie Site Sud - Service de Pneumologie
Amiens, 80054
Hôpital Avicenne
Bobigny, Seine-Saint Denis, 93000
Hopital Cote de Nacre
Caen, 14033
Groupement Hospitalier EST, Service de Pneumologie
Lyon, 69677 Cedex
APHM-Hôpital Nord
Marseille, 13015
Service de Pneumologie, Hôpital Européen Georges Pompídou (HEGP)
Paris, 75015
Hôpital Bichat
Paris, 75018
CHU Reims - Hôpital Maison Blanche
Reims, 51092
Hôpital Pontchaillou
Rennes, Ille-et-Vilaine, 35033
Hôpital Charles Nicolle-1 Rue de Germont
Rouen, 76000
CHU de Rouen - Hôpital Charles Nicolle
Rouen, 76031
Hôpital Larrey
Toulouse, 31059
CHRU Tours - Hôpital Bretonneau
Tours, 37044
Australia12 sites
Cairns Hospital
Cairns, Queensland, 5870
Royal Prince Alfred Hospital, Missenden Road
Camperdown, New South Wales, 2050
Lung Research Qld
Chermside, Queensland, 4032
Prince Charles Hospital
Chermside, Queensland, 4032
Respiratory Clinical Trials Pty Ltd
Kent Town, South Australia, 5067
Macquarie University
Macquarie Park, New South Wales, 2109
Alfred Health
Melbourne, Victoria, 3004
Austin Health
Melbourne, Victoria, 3004
Institute for Respiratory Health - Midland
Nedlands, Western Australia, 6009
Institute for Respiratory Health - Nedlands
Nedlands, Western Australia, 6009
Mater Misericordiae Ltd
South Brisbane, Queensland, 4101
Westmead Hospital, Corner of Hawkesbury and Darcy Road
Westmead, New South Wales, 2145
Spain11 sites
Hospital Universitari Vall d'Hebron
Barcelona, Barcelona, 08035
Hospital Clinic de Barcelona
Barcelona, Barcelona, 08036
Hospital Universitario Virgen de Las Nieves
Granada, Granada, 18014
Hospital Universitario de Bellvitge
L'Hospitalet de Llobregat, Barcelona, 08907
Hospital Universitario de La Princesa
Madrid, Madrid, 28006
Hospital General Universitario Gregorio Marañon
Madrid, Madrid, 28007
Hospital Clinico Universitario Virgen de la Arrixaca
Murcia, Murcia, 30120
Hospital Universitario Central de Asturias
Oviedo, Principality of Asturias, 33011
Hospital Universitario Son Espases
Palma de Mallorca, Balearic Islands, 07120
Hospital Universitario Marques de Valdecilla
Santander, Cantabria, 39008
Hospital Clinico Universitario de Santiago
Santiago de Compostela, 15706
Israel10 sites
Hillel Yaffe Medical Center
Hadera, 38100
Lady Davis Carmel Medical Center
Haifa, Haifa District, 34362
Rambam Medical Center - PPDS
Haifa, 3109601
Shaare Zedek Medical Center
Jerusalem, Jerusalem, 9103102
Hadassah Medical Center - PPDS
Jerusalem, Jerusalem, 91120
Meir Medical Center
Kfar Saba, Central District, 44281
Rabin Medical Center - PPDS
Petah Tikva, 4910000
Sheba Medical Center - PPDS
Ramat Gan, Tel Aviv, 52621
Kaplan Medical Center
Rehovot, Central District, 76100
Tel Aviv Sourasky Medical Center - PPDS
Tel Aviv, Southern District, 64239
Argentina9 sites
CINME S.A. - Centro de Investigaciones Metabolicas
Ciudad Autonoma de Buenos Aires, Buenos Aires, C1027AAP
Centro Medico Dra. De Salvo
Ciudad Autonoma de Buenos Aires, Buenos Aires, C1426ABP
Sanatorio Allende S.A.
Córdoba, Córdoba Province, 5021
Instituto Ave Pulmo - Fundación enfisema
Mar del Plata, Buenos Aires, 7600
Centro Médico INSARES
Mendoza, Mendoza Province, 5500
Instituto Médico Río Cuarto
Río Cuarto, Córdoba Province, 5800
Sanatorio Parque - Consultorios Externos
Rosario, Santa Fe Province, 2000
Centro Integral de Medicina Respiratoria
San Miguel de Tucumán, Tucumán Province, 4000
Investigaciones en Patologías Respiratorias
San Miguel de Tucumán, Tucumán Province, 4000
Belgium8 sites
AZORG vzw
Aalst, 9300
Hôpital Erasme
Anderlecht, Brussels Capital, 1070
Ziekenhuis Aan de Stroom
Antwerp, 2020
Cliniques Universitaires Saint-Luc
Brussels, 1200
UZ Leuven
Leuven, 3000
CHR de la Citadelle
Liège, 4000
CHU de Liège
Liège, 4000
CHU UCL Namur asbl - Site Godinne
Yvoir, Namur, 5530
Italy8 sites
Azienda Ospedaliero-Universitaria delle Marche
Ancona, 60126
Azienda Ospedaliero Universitaria Policlinico "G.Rodolico-San Marco"
Catania, Sicily, 95123
Presidio Ospedaliero GB Morgagni L Pierantoni
Forlì, Emilia-Romagna, 47121
Ospedale S. Giuseppe Multimedica
Milan, Lombardy, 20123
Azienda Ospedaliero Universitaria Di Modena Policlinico
Modena, 41124
Fondazione Policlinico Universitario A Gemelli-Rome
Roma, 00168
Fondazione PTV Policlinico Tor Vergata
Rome, 00133
Azienda Ospedaliera Universitaria Senese
Siena, Tuscany, 53100
South Korea8 sites
Gachon University Gil Medical Center
Incheon, 21565
CHA Bundang Medical Center, CHA University
Seongnam-si, Gyeonggido, 13496
Seoul National University Bundang Hospital
Seongnam-si, Gyeonggido, 13620
Asan Medical Center
Seoul, Seoul Teugbyeolsi, 05505
SMG - SNU Boramae Medical Center
Seoul, Seoul Teugbyeolsi, 7061
Korea University Anam Hospital
Seoul, 02841
The Catholic University of Korea - Eunpyeong St. Mary's Hospital
Seoul, 03312
Samsung Medical Center - PPDS
Seoul, 06351
Germany6 sites
Zentralklinik Bad Berka GmbH
Bad Berka, 99437
Fachkrankenhaus Coswig
Coswig, 01640
Universitätsmedezin Essen Ruhrlandklinik Westdeutsches Lungenzentrum am Universitätsklinikum Essen gGmbH
Essen, North Rhine-Westphalia, 45239
Klinik Löwenstein GmbH
Löwenstein, Baden-Wurttemberg, 74245
LMU Klinikum der Universität
München, 81377
RoMed Klinikum Rosenheim
Rosenheim, Bavaria, 83022
Chile4 sites
Instituto Nacional Torax
Santiago, Santiago Metropolitan, 7500691
Fundación Médica San Cristobal
Santiago, Santiago Metropolitan, 7630000
Centro de Investigacion del Maule SpA
Talca, Maule Region, 3465586
Oncocentro APYS
Viña del Mar, Valparaiso, 2520598
Peru4 sites
Hospital Nacional Adolfo Guevara Velasco
Cusco, Departamento de Cusco, 8003
Hospital de Chancay y Servicios Basicos deSalud
Huaral, Lima region, 15131
Clinica Ricardo Palma
Lima, Lima Province, 15036
Hospital Central de la Fuerza Aerea Del Peru
Lima, 15046
Taiwan4 sites
Kaohsiung Medical University - Chung-Ho Memorial Hospital
Kaohsiung City, Samin District, 80756
E-DA hospital
Kaohsiung City, 82445
Far Eastern Memorial Hospital
New Taipei City, 220
Taipei Veterans General Hospital
Taipei, 11217
Denmark3 sites
Aarhus University Hospital - Department of Respiratory Diseases and Allergy, Research Unit
Aarhus N, 8200
Gentofte Hospital - Lungemedicinsk forskning
Hellerup, 2900
Odense University Hospital - Department of Respiratory Medicine J.
Odense C, 5000
Mexico3 sites
Instituto Nacional De Enfermedades Respiratorias Ismael Cosio Villegas
Mexico City, Mexico City, 14080
Unidad de Investigación Clínica en Medicina, S.C.
Monterrey, Nuevo León, 64060
Hospital Universitario "Dr. José Eleuterio González"
Monterrey, Nuevo León, 64460
Netherlands3 sites
Zuyderland Medisch Centrum
Heerlen, Limburg, 6419 PC
St. Antonius Ziekenhuis
Nieuwegein, Utrecht, 3435 CM
Erasmus MC
Rotterdam, South Holland, 3015 GD
New Zealand2 sites
Canterbury Respiratory Research Group
Christchurch, Canterbury, 8013
Respiratory Medicine
Hamilton, Waikato Region, 3204
About this study
Official title: 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.
Read the 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 idiopathic pulmonary fibrosis (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.
- Being tested
- Placebo, Inhaled Treprostinil, Treprostinil Ultrasonic Nebulizer
- Medical subject headings
- Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PlaceboDrug
Placebo administered QID
Inhaled TreprostinilDrug
Also called Tyvaso
Inhaled treprostinil (6 mcg/breath) administered QID
Treprostinil Ultrasonic NebulizerDevice
Treprostinil ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath.
| Study group | Role | What they receive |
|---|---|---|
| Placebo | Placebo comparator | Matching placebo inhaled using an ultrasonic nebulizer QID Receives: Drug: Placebo; Device: Treprostinil Ultrasonic Nebulizer |
| Inhaled Treprostinil | Experimental | 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. Receives: Drug: Inhaled Treprostinil; Device: Treprostinil Ultrasonic Nebulizer |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Baseline to Week 52
Secondary outcomes (6)
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. The number of participants with clinical worsening was reported. The time to first clinical worsening event was analyzed by stratified log-rank test (p-value) and presented with the hazard ratio calculated by proportional hazards model with treatment and baseline background therapy as explanatory variables.
Measured: Baseline to Week 52
Time to First Acute Exacerbation of IPF
An acute exacerbation of IPF is defined as an acute, clinically significant, respiratory deterioration characterized by evidence of new widespread alveolar abnormality. The number of participants with an exacerbation of IPF was reported. The time to first acute exacerbation of IPF was analyzed by stratified log-rank test (p-value) and presented with the hazard ratio calculated by proportional hazards model with treatment and baseline background therapy as explanatory variables.
Measured: Baseline to Week 52
Overall Survival at Week 52
Vital status was assessed for all subjects at Week 52, including those who discontinued the study prematurely. The number of deaths by Week 52 was reported. The time to death was analyzed by stratified log-rank test (p-value) and presented with the hazard ratio calculated by proportional hazards model with treatment and baseline background therapy as explanatory variables. Note: Participants who discontinued from the study early had their time to death censored at Day 373 or last contact date when known to be alive (whichever occurred first), and participants with lung transplantation had their time to death censored at lung transplant date. Therefore, the number of deaths for this outcome measure differ from the overall number on deaths (reported in the Adverse Events section).
Measured: 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.
Measured: Baseline to Week 52
Change in K-BILD Total Score From Baseline to Week 52
The King's Brief Interstitial Lung Disease Questionnaire (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). Each of the 15 questions is scored from 1 (worst score) to 7 (best score). The scores for the 15 questions are added together and converted into a Total Score from 0 to 100. Higher scores indicate a better quality of life.
Measured: 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.
Measured: Baseline to Week 52
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Feb 2022
- Study start12 Sep 2022
- Primary completion30 Jun 2025
- Study completion30 Jun 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Idiopathic Pulmonary FibrosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 597 participants (actual)
Sponsor and investigators
- Lead sponsor
- United Therapeutics
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05255991
- Sponsor's protocol ID
- RIN-PF-303
- Acronym
- TETON-2
- Status last verified
- Sep 2026
- First submitted
- 15 Feb 2022
- Last updated
- 15 Oct 2026
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- Yes
Publications
Nathan SD, Smith P, Deng C, Golden J, Reynaud-Gaubert M, Farr G, Bregman B, Crossno PF, Harari S, Gupta N, Jouneau S, Adir Y, Molina-Molina M, Breytenbach N, Peterson L, Bell H, Zywot E, Rao Y, Flaherty KR, Cottin V, Behr J; TETON-1 and TETON-2 Trial Investigators. Combined results of the TETON-1 and TETON-2 Trials of Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2026 Sep 23:aamag507. doi: 10.1093/ajrccm/aamag507. Online ahead of print.
PubMed 42776606Nathan SD, Smith P, Deng C, De Salvo M, Wuyts W, Pavie-Gallegos J, Song JW, Kramer MR, King CS, Mackintosh JA, Chambers D, Miranda GV, Breytenbach N, Peterson L, Bell H, Flaherty KR, Behr J, Cottin V; TETON-2 Trial Investigators. Inhaled Treprostinil for Idiopathic Pulmonary Fibrosis. N Engl J Med. 2026 Jul 9;395(2):127-137. doi: 10.1056/NEJMoa2512911. Epub 2026 Mar 11.
PubMed 41812190