Phase 3 Randomized, Double-blind, Placebo-controlled Study of Inhaled Treprostinil in Progressive Pulmonary Fibrosis Patients
- Trial ID
- 2023-504904-26-00
- Protocol
- RIN-PF-305
- Sponsor
- United Therapeutics Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **superiority** of inhaled treprostinil compared to placebo in terms of the change in absolute forced vital capacity (FVC) from baseline to Week 52 in subjects with **Progressive Pulmonary Fibrosis** (PPF). This is clinically relevant as FVC is a critical measure of lung function, and improvements in FVC can indicate a slowing of disease progression, which is vital for patient outcomes in PPF.
Secondary objectives include evaluating the effect of inhaled treprostinil against placebo on several parameters:
- Time to clinical worsening and time to first acute exacerbation of interstitial lung disease (ILD)
- Overall survival
- Percentage predicted FVC
- King’s Brief Interstitial Lung Disease Questionnaire (KBILD) score
- Diffusion capacity of lungs for carbon monoxide (DLCO)
- Absolute FVC
- N-terminal pro-brain natriuretic peptide (NT-proBNP)
- Resting supplemental oxygen use
- Safety of inhaled treprostinil
Participants
The clinical trial involves a total of **483 participants** diagnosed with **Progressive Pulmonary Fibrosis** (PPF). The study population includes both male and female subjects, aged **18 years and older**, who have radiological evidence of pulmonary fibrosis exceeding 10% extent on an HRCT scan within the previous 12 months. Participants were selected based on their ability to communicate effectively with study personnel and their willingness to comply with protocol requirements. The trial includes individuals who are either on treatment with nintedanib or pirfenidone for at least 90 days prior to the baseline or not planning to initiate these treatments during the study. Additionally, subjects treated with immunosuppressive agents must have been on treatment for at least 120 days prior to the baseline. Women of childbearing potential are required to use highly effective contraception methods, while males with partners of childbearing potential must agree to use a condom during the study. The trial population is considered vulnerable, and the selection process ensures that participants are reliable and likely to cooperate with the study's requirements.
Plans and Procedures
The clinical trial is a **randomized, double-blind, placebo-controlled, Phase 3 study** designed to evaluate the efficacy and safety of inhaled **Treprostinil** in participants with **Progressive Pulmonary Fibrosis** (PPF). The primary objective is to assess the superiority of inhaled Treprostinil over placebo by measuring the change in absolute forced vital capacity (FVC) from baseline to Week 52. The trial is expected to commence recruitment on March 1, 2025, and conclude by August 31, 2027, with a total duration of 52 weeks for each participant.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on specific criteria, such as age, radiological evidence of pulmonary fibrosis, and previous treatment history. Following successful screening, participants will be randomized to receive either the active treatment or placebo. The trial includes multiple follow-up visits at Weeks 16, 28, and 40 to monitor changes in FVC, adverse events, and other clinical parameters. The end-of-study visit at Week 52 will finalize data collection and assess the primary and secondary endpoints, including overall survival and changes in various clinical measures.
Participant involvement is expected to last for the entire 52-week period unless early termination is warranted. Conditions that may lead to early withdrawal include significant adverse events, non-compliance with study procedures, or withdrawal of consent. The study will ensure that all participants are monitored closely to maintain the integrity of the trial and the safety of the participants.
Treatment
The clinical trial involves the administration of **Treprostinil**, a **nebuliser solution** developed by United Therapeutics Corporation. Treprostinil is a chemically synthesized active substance intended for **inhalation use**. The maximum daily dose of Treprostinil is 360 micrograms, with a total maximum dose of 393,120 micrograms over a treatment period of 52 weeks. The solution is administered via a nebuliser, ensuring precise delivery to the respiratory system. The dosing schedule is designed to maintain therapeutic levels of the drug, and participant compliance is monitored through regular assessments and adherence checks.
The study also includes a **placebo** group, receiving a nebuliser solution identical in appearance and administration to the Treprostinil solution, but devoid of the active substance. This placebo solution serves as a control to evaluate the efficacy and safety of Treprostinil in participants with progressive pulmonary fibrosis. The placebo is administered with the same frequency and via the same route as the active treatment, ensuring blinding and consistency across the study groups. Compliance with the placebo regimen is similarly monitored to ensure the integrity of the trial results.
Efficacy
The efficacy of inhaled **Treprostinil** in participants with Progressive Pulmonary Fibrosis (PPF) will be assessed through a randomized, double-blind, placebo-controlled, Phase 3 clinical trial. The primary endpoint for evaluating efficacy is the change in absolute Forced Vital Capacity (FVC) from baseline to Week 52. Secondary endpoints include time to first clinical worsening event, time to first acute exacerbation of interstitial lung disease (ILD), overall survival at Week 52, and changes from baseline in % predicted FVC, K-BILD score, DLCO, NT-proBNP, and resting supplemental oxygen use at Week 52. Additional assessments will include adverse events, serious adverse events, clinical laboratory parameters, vital signs, and 12-lead electrocardiograms.
Measurements will be collected at specified timepoints, including Weeks 16, 28, 40, and 52, using validated scales and laboratory tests. The trial aims to determine the superiority of inhaled Treprostinil over placebo in improving lung function and overall health outcomes in subjects with PPF. The study will ensure rigorous data collection and analysis to support the evaluation of the treatment's efficacy and safety profile over the 52-week treatment period.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Subject gives voluntary informed consent to participate in the study.
- Subject is ≥18 years of age, inclusive, at the time of signing informed consent.
- Subject has radiological evidence of pulmonary fibrosis of >10% extent on an HRCT scan in the previous 12 months (confirmed by central review).
- Subject has a diagnosis of PPF (other than IPF) that fulfills at least 1 of the following criteria for progression within 24 months of screening despite standard treatment of ILD, as assessed by the Investigator: a) Clinically significant decline in % predicted FVC based on ≥10% relative decline b) Marginal decline in % predicted FVC based on ≥5% to <10% relative decline combined with worsening of respiratory symptoms c) Marginal decline in % predicted FVC based on ≥5% to <10% relative decline combined with increasing extent of fibrotic changes on chest imaging d) Worsening of respiratory symptoms as well as increasing extent of fibrotic changes on chest imaging
- FVC ≥45% predicted at Screening (confirmed by central review).
- Subjects must be on 1 of the following: a) On nintedanib or pirfenidone for ≥90 days prior to Baseline and in the Investigator’s opinion, are planning to continue treatment through the study b) Not on treatment with nintedanib or pirfenidone for ≥90 days prior to Baseline and in the Investigator’s opinion, not planning to initiate either treatment during the study. Concomitant use of both nintedanib and pirfenidone is not permitted.
- Subjects treated with immunosuppressive agents (eg, mycophenolate, methotrexate, azathioprine, oral corticosteroids, rituximab) need to be on treatment for at least 120 days prior to Baseline and, in the Investigator’s clinical opinion, must be refractory to treatment.
- Women of childbearing potential must be nonpregnant (as confirmed by a urine pregnancy test at Screening and Baseline) and nonlactating, and will agree to 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. 1)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 salpingectomy, or bilateral oophorectomy) or postmenopausal (defined as amenorrhea for at least 12 consecutive months) are not considered to be of reproductive potential.
- Males with a partner of childbearing potential must agree to 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.
Exclusion Criteria
- Subject is pregnant or lactating.
- Acute pulmonary embolism within 90 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.
- In the opinion of the Investigator, life expectancy <12 months due to ILD or a concomitant illness.
- Subject has primary obstructive airway physiology (forced expiratory volume in 1 second/FVC <0.70 at Screening) or greater extent of emphysema than fibrosis on HRCT (confirmed by central review).
- Subject has a diagnosis of IPF.
- 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.
- 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 (PDE5Is), soluble guanylate cyclase stimulators , or activin signaling inhibitors (sotatercept) within 60 days prior to Baseline. As needed use of a PDE5I for erectile dysfunction is permitted, provided no doses are taken within 48 hours prior to any studyrelated efficacy assessments.
- Subject is receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline
- Exacerbation of ILD 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 ILD or a pulmonary or upper respiratory infection, subjects must have been discharged more than 90 days prior to Baseline to be eligible.
- Subject has uncontrolled cardiac disease, defined as myocardial infarction within 6 months prior to Baseline or unstable angina within 30 days prior to Baseline.
- 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 noninterventional, observational, or registry studies are eligible.
- Subject has received nerandomilast within 60 days prior to Baseline.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Recruiting | 01 Mar 2025 | 51 |
 France | Recruiting | 01 Mar 2025 | 40 |
 Germany | Recruiting | 01 Mar 2025 | 55 |
 Italy | Recruiting | 01 Mar 2025 | 51 |
 Spain | Recruiting | 01 Mar 2025 | 45 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Treprostinil | Test | NEBULISER SOLUTION | INHALATION USE | 360 | 52 | PRD9910879 |
The Placebo Nebuliser Solution is a solution dosage form for nebulisation identical to
Treprostinil Nebuliser Solution drug product except for the absence of the treprostinil drug
substance. | Placebo | N/A | — | — | — | N/A |