Early Intervention With Inhaled Treprostinil Among Patients With Exercise-Induced Pulmonary Hypertension (EPIH)

1.1 Purpose/Specific Aims This pilot study aims to determine whether early treatment of exercise-induced pulmonary hypertension with inhaled Treprostinil can improve pulmonary vascular hemodynamics, preserve cardiopulmonary reserve, and delay progression to overt resting pulmonary hypertension in patients with interstitial lung disease (ILD) or connective tissue disease (CTD).

A. Objectives

Primary Objective:

• To evaluate the effect of inhaled treprostinil on exercise pulmonary vascular resistance (PVR) at 6 months in patients with PH-ILD or PH-CTD exercise-induced pulmonary hypertension.

Secondary Objectives:

• To assess the effect of inhaled treprostinil on additional exercise hemodynamic parameters, including mPAP/CO slope, right ventricular stroke work index (RVSWI), and pulmonary arterial compliance at 6 months.
• To evaluate the effect of inhaled treprostinil on functional capacity measured by 6- minute walk distance at 6 months.
• To assess the effect of inhaled treprostinil on exercise tolerance and dyspnea measured by the dyspnea (BORG) questionnaire at 6 months.
• To evaluate the safety and tolerability of inhaled treprostinil in patients with exercise induced PH.
• To assess the proportion of patients progressing to resting PH at 12 months (if the studyextends based on positive 6-month results).
• To evaluate sustained hemodynamic and functional benefits at 12 months (if the study is extended).

Hypotheses / Research Question(s) Treatment with inhaled treprostinil in patients with PH-ILD or PH-CTD with exercise-induced pulmonary hypertension will result in improvement in pulmonary vascular physiology and clinical outcomes. Specifically, inhaled treprostinil administered over 6 months is hypothesized to reduce exercise pulmonary vascular resistance (PVR), improve exercise hemodynamic parameters including mPAP/CO slope, right ventricular stroke work index, and pulmonary arterial compliance, enhance functional capacity as measured by 6-minute walk distance, and improve exercise tolerance and dyspnea as assessed by BORG scores. Inhaled treprostinil is further hypothesized to be safe and well tolerated in this population and may reduce progression to resting pulmonary hypertension, with sustained hemodynamic and functional benefits observed at 12 months among patients continuing therapy

Research Procedures Screening: Resting RHC on all ILD and CTD patients to exclude resting PH.

Baseline: Exercise RHC + iCPET to identify exercise PH and then select eligible patients. Once a matched pair is identified, one participant will be assigned to receive inhaled treprostinil and the other will receive standard of care. Assignment within each matched pair will be determined using a simple allocation method (such as alternating assignment) to reduce bias.

Treatment Period: 6 months with monthly visits (or more if needed) with 6MWT, BNP, safety assessments.

Primary Endpoint: Month 6 exercise RHC + iCPET, functional and quality of life assessments.

Go/No-Go Decision: Extend to 12 months if ≥ 1.0 WU reduction in peak VR, acceptable safety, ≥ 70% completion rate.

Inclusion criteria

• Age ≥18 years
• ILD diagnosis or CTD diagnosis
• WHO Functional Class II-III
• Resting RHC:

• mPAP ≤20 mmHg
• PVR ≤2 WU
• PAWP ≤15 mmHg
• Exercise-induced pulmonary hypertension on iCPET
• Able to provide informed consent

Exclusion criteria

• Resting pulmonary hypertension
• Significant left heart disease
• CTEPH
• Acute PE within 6 months
• Current PAH-targeted therapy
• Pregnancy or breastfeeding
• Severe renal or hepatic impairment
• Inability to perform exercise testing
• Contraindication to RHC
• Treprostinil hypersensitivity