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INCREASE TRIAL | Inhaled Treprostinil

Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease (PH-ILD)

Phase III, multicenter, double-blind, randomized, placebo-controlled, parallel-group trial

Conclusion

In people with PH-ILD, treatment with inhaled treprostinil improved exercise capacity and lowered the risk of clinical worsening

Study Overview

A 16-week study evaluating the safety and efficacy of inhaled treprostinil in patients with PH-ILD

Inhaled treprostinil
163
Placebo
163
93 Centers
326 Participants
≥9 Breaths Target dose, 4x/day
3
Breaths 18µg, 4x/day

Starting dose

+1
Breaths 6µg, 4x/day

Max. titration (every 3rd day)

12
Breaths 72µg, 4x/day

Max. dose*

*Participants who reached 10–12 breaths at Week 16:

58%

Types of interstitial lung diseases

ILD subtypes in the trial: 45% idiopathic interstitial pneumonia (IIP), which included idiopathic pulmonary fibrosis (IPF), 25 % combined pulmonary fibrosis and emphysema (CPFE), 22% connective tissue disease (CTD), and 8% other. Other included chronic hypersensitivity pneumonitis (CHP).

ILDs included those with idiopathic, environmental, autoimmune and occupational origins

Baseline Characteristics

  • Median PVR 5.3 wu Range 3.0–18.1
  • Average Age 67 yrs Range 26–90
  • Median 6MWD 259 m Range 30–538
  • Supplemental oxygen use 71%
  • Antifibrotic therapy 23%

Result

Primary Endpoint

6MWD

At week 16, inhaled treprostinil improved exercise capacity compared to placebo

31m difference

95% CI, 16.85–45.39p < 0.001

Mean (+/-SE) Change from Baseline in 6-Minute Walk Distance
A line graph of mean (SE) change in 6MWD from week 0 to 16. The lines separate at week 8, with placebo sustaining a negative walk change and inhaled treprostinil distance improving over time.

Secondary Endpoints

NT-proBNP

At week 16, NT-proBNP levels improved in the inhaled treprostinil group and worsened in the placebo group

Percent change† from baseline to week 16
At week 16, NT-proBNP decreased 15% with inhaled treprostinil and increased 46% with placebo, treatment ratio of 0.58 (95% CI, 0.47 – 0.72; p < 0.001). Percent change is the difference in geometric mean ratio compared to baseline.

Treatment ratio 0.58
(95% CI, 0.47–0.72); p < 0.001

†Difference (treatment vs. placebo) in geometric mean ratio to baseline

NT-proBNP levels from baseline to week 16
Median (IQR) NT-proBNP levels at Week 0, 8, and 16. Median NT-proBNP levels decreased over time for the inhaled treprostinil treatment group and increased for the placebo group.

Clinical Worsening

Treatment with inhaled treprostinil was associated with a lower risk of clinical worsening

Participants with clinical worsening by 16 weeks
At Week 16, 23% (n = 37) of the inhaled treprostinil treatment group experienced clinical worsening compared to 33% (n = 54) of the placebo group.

Some data is censored in the event curve.

Time to first clinical worsening event
A Kaplan-Meier curve of the 16-week study showed a 39% reduction in risk of clinical worsening for inhaled treprostinil compared to placebo, HR 0.61 (95% CI, 0.4 – 0.92, p = 0.04).

Lowered risk of clinical worsening for inhaled treprostinil vs. placebo over 16 weeks

39% reduction

HR: 0.61 95% CI: 0.4, 0.92 p = 0.04

Clinical worsening events

6MWD Decrease > 15% disease-related decline from baseline
Hospitalization for cardiopulmonary indication
Lung Transplant
Death
Exacerbations**
39% Placebo
27% Treprostinil

Fewer patients in the treprostinil group had exacerbations of underlying lung disease

** Acute, clinically significant respiratory deterioration characterized by evidence of new widespread alveolar abnormality

The use of inhaled treprostinil was not associated with any decrement in lung function or oxygenation.

The safety profile of inhaled treprostinil was consistent with previous studies in people with pulmonary arterial hypertension (PAH).

Variable Inhaled treprostinil (n=163) Placebo (n=163)
Most frequently occurring adverse events – no. of patients (%)‡
Cough 71 (44) 54 (33)
Headache 45 (28) 32 (20)
Dyspnea 41 (25) 51 (31)
Dizziness 30 (18) 23 (14)
Nausea 25 (15) 26 (16)
Fatigue 23 (14) 23 (14)
Diarrhea 22 (13) 19 (12)
Throat irritation 20 (12) 6 (4)
Oropharyngeal pain 18 (11) 4 (3)
NT-proBNP increased 9 (6) 25 (15)
AEs leading to discontinuation 16 (10) 13 (8)

‡ Shown are the most frequently occurring adverse events occurring in more than 10% of patients in either group in the safety population, which comprised all patients who underwent randomization and received at least one dose of treprostinil or placebo