A Study of Inhaled Treprostinil in Subjects with Idiopathic Pulmonary Fibrosis (TETON) (H-51478)

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

Indication: Idiopathic pulmonary fibrosis (IPF)

Primary Objective: The primary objective of the study is to evaluate the safety and efficacy of inhaled treprostinil in subjects with IPF.

Study Design: This is a Phase 3, randomized, double-blind, placebo-controlled, efficacy and safety study of subjects with IPF treated with inhaled treprostinil over a 52-week period.

Route of Administration: Inhaled Treprostinil inhalation solution or placebo will be administered using the TD-300 ultrasonic nebulizer (Tyvaso Inhalation System®).

Procedures: Subjects will be assessed during the Screening and Baseline Visits to determine eligibility for the study. Once eligible, 6 Treatment Period visits to the clinic will be required at Weeks 4, 8, 16, 28, 40, and 52. Subjects will also be contacted by telephone or email at least weekly until Week 16 and monthly thereafter in-between study visits to discuss study drug titration, assess study drug tolerability, monitor AEs, and document changes to concomitant medications. Subjects who discontinue study drug prematurely before Week 52 will be encouraged to remain in the study and attend the remaining scheduled study visits up to and including Week 52; a Premature Study Drug Discontinuation Visit should be conducted as soon as possible, and as best as possible prior to final dose of study drug. In the event a subject withdraws from the study, an Early Termination (ET) Visit will be conducted; all assessments planned for the Week 52 Visit will be conducted during the ET Visit, as applicable. ET Visit assessments should be completed before the final dose of study drug if at all possible. Every attempt will be made to assess vital status for all subjects at Week 52, including those who discontinue the study prematurely or who withdraw consent. 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.

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 HRCT (performed within the previous 12 months) and if available, surgical lung biopsy. HRCT imaging must be “consistent with UIP,” defined as meeting either criteria A, B, and C; or criteria A and C; or criteria B and C below:
   a. Subpleural and basal predominant honeycombing
   b. Subpleural and basal predominant reticular pattern with peripheral traction bronchiectasis or traction bronchiolectasis
   c. Absence of atypical features (eg, predominant ground-glass opacity, nodules, consolidation, etc). If ground-glass opacity is present, it must be less than the accompanying reticular pattern. Subjects with HRCT features deemed indeterminate for IPF (subpleural and basal predominant, subtle, reticulating pattern of fibrosis) may be considered for inclusion if coupled with a histopathological pattern of “UIP” or “probable UIP” on surgical lung biopsy and confirmed by central review.
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 do 1 of the following:
   a. Abstain from intercourse (when it is in line with their preferred and usual lifestyle)
   b. Use 2 medically acceptable, highly effective forms of contraception for the duration of the study, and at least 30 days after discontinuing study drug.
   c. Medically acceptable, highly effective forms of contraception can include approved hormonal contraceptives (oral, injectable, and implantable) and barrier methods (such as a condom or diaphragm) when used with a spermicide. Women who are successfully sterilized (including hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or postmenopausal (defined as amenorrhea for at least 12 consecutive months) are not considered to be of reproductive potential.
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:
   a. Azathioprine (AZA), cyclosporine, mycophenolate mofetil, tacroliumus, oral corticosteroids (OCS) >20 mg/day or the combination of OCS+AZA+N-acetylcysteine within 30 days prior to Baseline.
   b. Cyclophosphamide within 60 days prior to Baseline
   c. 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.